11-Year-Old Girl From Brazil Died Four Days After She Was Threatened and Forced to Take COVID Vaccine
THE VACCINE DEATH REPORT
EVIDENCE OF MILLIONS OF DEATHS AND HUNDREDS OF MILLIONS OF SERIOUS ADVERSE EVENTS RESULTING FROM THE EXPERIMENTAL COVID INJECTIONS
The Vaccine Death Report shows all the scientific evidence that millions of innocent people lost their lives and hundreds of millions are suffering crippling side effects, after being injected with the experimental covid injections. The report exposes the strategic methods used by governments and health agencies to hide 99% of all vaccine injuries and deaths. You will also learn who is really behind all of this, and what their true agenda is.
The report also shows horrifying lab results from microscopic investigation of some vaccine vials: living creatures with tentacles, as well as self-assembling nanorobots. See pictures:
These creatures and self-assembling and self-replicating nanobots are present in some of the vaccines!
The Vaccine Death Report contains a tremendous amount of critical information, that you will find nowhere else in such a comprehensive and well organized format. It ends with a strong message of hope, that will greatly empower you.
This report is a critical alarm call to the world. Download it now, and distribute it far and wide.
Now if you have been paying attention to my blogs, you will already see what is happening here. These scientists ( if they exist ) are well paid to say whatever they are told to say.
The vaccines ( Kill shots ) have been causing almost every blood disorder on the planet. Although some are not reported because the doctors think it’s just normal cancer of the blood because of the backlog.
But none can deny that Myocarditis is a direct result of the vaccine ( kill shot )
Once a rare disorder in those under 24 years of age and even more rare in those under 14 years of age has become a vivid scene for undertaken. But more than that it has become a sad and devastating reality for thousands of parents and sisters and brothers and families of those who have died. Over a thousand professional sports players have collapsed or died in the middle of a game.
I lost 9 very good friends last year and many acquaintances. This year already I have lost one family member and 4 acquaintances. That’s 14 people. One young girl who was a friend of my daughter’s age 23, died 7 days after her vaccine of a brain haemorrhage. One very close friend died of cancer a short time after his vaccine. His vaccine brought back his cancer so quickly and aggressively that it killed him within a week. I was outside his hospital door unable to go in a few hours before he died. He was 55 years old.
Anyway back to myocarditis. Monkeypox is being made out to be a small matter at the moment. But I can assure you that it will be a pandemic. They are building up to it slowly because covid is dying out in people’s minds because of the work people called conspiracy theorists do.
So because myocarditis is proven to be the cause of vaccine damage and there’s no informed consent, the government are being held reliable. And we all know that the government do not like to give the people the money that they are entitled to.
Even the emergency use authorisation ( EUA ) should not still be active because the pandemic is over. But still, even though they know that the kill shots are causing millions of deaths and millions of injuries, they have used an illegal EUA to allow untested kill shots knowing that thousands of you will die. But of course, it’s all to do with your health.
Lockdown and all the other restrictions were killers that didn’t work too. Or Lockstep I like to call it. Did you know that 192 countries all scrapped their decades-old pandemic mandates at the same time and mysteriously all followed the same New rules set out by the 192 countries WITHOUT supposedly contacting any of the other leaders etc?
Every country is the same. Except for China! They had the lab leak and there were videos of people falling dead in the street. 🙄
But now look at them. They did their bit and didn’t have to pretend anymore.
There is no smallpox in the world!
The approved drug causes heart damage, myocarditis, and pericarditis, but the DOD, in its quest to decimate the American military allowed it in 2018.
The US government has millions of doses, even though there aren’t confirmed smallpox cases.
And the UK just ordered tens of thousands of the monkeypox kill shots as planned but, Don’t work. They will cause the deaths that are mentioned and just like Covid, only the vaccinated will get so-called monkeypox, become unwell or die. But this won’t target the elderly, this will target anyone who has no critical thinking and is clouded by the media telling them they are conspiracy theories.
here’s a paragraph from a book on viruses. The good thing about books is Google and Wikipedia can not edit them. Have a read on monkeypox
There is a video here you can watch by Dr Jane Ruby.
The link below for a video if you would like to hear a video from a professional.
Today you will hear Dr Jane Ruby Show, where she speaks about the latest combination of Smallpox/Monkeypox vaccines, approved four years ago!
Thank you for reading.
Please share this with everyone. I’m not after the followers so they don’t have to sign up and like them. I’m doing my bit by researching everything I have sent to myself, watching government websites worldwide and the CDC, WHO, WEF, NIH, CHAN ZUCKERBERG and many more websites.
Remember that the Americans are blaming Russia for everything. You name it and it will be Russian disinformation.
Well if you look at my blog “ what’s happening really in Ukraine “ you will see firsthand footage of the citizens speaking out, and plenty of other Russian Ukraine war and other updates.
Please remember to share and stop this fake monkeypox kill shot from being put into every one. Save lives, don’t let them take the shot.
Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Ivermectin induces apoptosis and autophagy is mutually regulated. Interestingly, ivermectin can also inhibit tumor stem cells and reverse multidrug resistance and exerts the optimal effect when used in combination with other chemotherapy drugs.
Abbreviations: ASC, Apoptosis-associated speck-like protein containing a CARD; ALCAR, acetyl-L-carnitine; CSCs, Cancer stem cells; DAMP, Damage-associated molecular pattern; EGFR, Epidermal growth factor receptor; EBV, Epstein-Barr virus; EMT, Epithelial mesenchymal-transition; GABA, Gamma-aminobutyric acid; GSDMD, Gasdermin D; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HER2, Human epidermal growth factor receptor 2; HMGB1, High mobility group box-1 protein; HSP27, Heat shock protein 27; LD50, median lethal dose; LDH, Lactate dehydrogenase; IVM, Ivermectin; MDR, Multidrug resistance; NAC, N-acetyl-L-cysteine; OCT-4, Octamer-binding protein 4; PAK1, P-21-activated kinases 1; PAMP, Pathogen-associated molecular pattern; PARP, poly (ADP- ribose) polymerase; P-gp, P-glycoprotein; PRR, pattern recognition receptor; ROS, Reactive oxygen species; STAT3, Signal transducer and activator of transcription 3; SID, SIN3-interaction domain; siRNA, small interfering RNA; SOX-2, SRY-box 2; TNBC, Triple-negative breast cancer; YAP1, Yes-associated protein 1
Chemical compounds reviewed in this article: ivermectin(PubChem CID：6321424), avermectin(PubChem CID：6434889), selamectin(PubChem CID：9578507), doramectin(PubChem CID：9832750), moxidectin(PubChem CID：9832912)
Keywords: ivermectin, cancer, drug repositioning
Ivermectin is a macrolide antiparasitic drug with a 16-membered ring that is widely used for the treatment of many parasitic diseases such as river blindness, elephantiasis and scabies. Satoshi ōmura and William C. Campbell won the 2015 Nobel Prize in Physiology or Medicine for the discovery of the excellent efficacy of ivermectin against parasitic diseases. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. This suggests that ivermectin may be an anticancer drug with great potential. Here, we reviewed the related mechanisms by which ivermectin inhibited the development of different cancers and promoted programmed cell death and discussed the prospects for the clinical application of ivermectin as an anticancer drug for neoplasm therapy.
Ivermectin(IVM) is a macrolide antiparasitic drug with a 16-membered ring derived from avermectin that is composed of 80% 22,23-dihydroavermectin-B1a and 20% 22,23-dihydroavermectin-B1b . In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [, , , ] (Fig. 1 ). IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 . It has a good effect on the treatment of parasitic diseases such as river blindness, elephantiasis, and scabies. The discoverers of IVM, Japanese scientist Satoshi ōmura and Irish scientist William C. Campbell, won the Nobel Prize in Physiology or Medicine in 2015 [7,8]. IVM activates glutamate-gated chloride channels in the parasite, causing a large amount of chloride ion influx and neuronal hyperpolarization, thereby leading to the release of gamma-aminobutyric acid (GABA) to destroy nerves, and the nerve transmission of muscle cells induces the paralysis of somatic muscles to kill parasites [9,10]. IVM has also shown beneficial effects against other parasitic diseases, such as malaria [11,12], trypanosomiasis , schistosomiasis , trichinosis  and leishmaniasis .
The chemical structures of ivermectin and other avermectin family compounds in this review.
IVM not only has strong effects on parasites but also has potential antiviral effects. IVM can inhibit the replication of flavivirus by targeting the NS3 helicase ; it also blocks the nuclear transport of viral proteins by acting on α/β-mediated nuclear transport and exerts antiviral activity against the HIV-1 and dengue viruses . Recent studies have also pointed out that it has a promising inhibitory effect on the SARS-CoV-2 virus, which has caused a global outbreak in 2020 . In addition, IVM shows potential for clinical application in asthma  and neurological diseases . Recently scientists have discovered that IVM has a strong anticancer effect.
Since the first report that IVM could reverse tumor multidrug resistance (MDR) in 1996 , a few relevant studies have emphasized the potential use of IVM as a new cancer
treatment [, , , , ]. Despite the large number of related studies, there are still some key issues that have not been resolved. First of all, the specific mechanism of IVM-mediated cytotoxicity in tumor cells is unclear; it may be related to the effect of IVM on various signaling pathways, but it is not very clear overall. Second, IVM seems to induce mixed cell death in tumor cells, which is also a controversial issue. Therefore, this review summarized the latest findings on the anticancer effect of IVM and discussed the mechanism of the inhibition of tumor proliferation and the way that IVM induces tumor programmed cell death to provide a theoretical basis for the use of IVM as a potential anticancer drug. As the cost of the research and development of new anticancer drugs continues to increase, drug repositioning has become increasingly important. Drug repositioning refers to the development of new drug indications that have been approved for clinical use . For some older drugs that are widely used for their original indications and have clinical data and safety information, drug repositioning allows them to be developed via a cheaper and faster cycle and to be used more effectively in clinical use clinically . Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment.
2. The role of IVM in different cancers
2.1. Breast cancer
Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. The incidence of breast cancer has increased each year, and it has become one of the female malignant tumors with the highest incidence in globally. On average, a new case is diagnosed every 18 seconds worldwide [30,31]. After treatment with IVM, the proliferation of multiple breast cancer cell lines including MCF-7, MDA-MB-231 and MCF-10 was significantly reduced. The mechanism involved the inhibition by IVM of the Akt/mTOR pathway to induce autophagy and p-21-activated kinase 1(PAK1)was the target of IVM for breast cancer . Furthermore, Diao’s study showed that IVM could inhibit the proliferation of the canine breast tumor cell lines CMT7364 and CIPp by blocking the cell cycle without increasing apoptosis, and the mechanism of IVM may be related to the inhibition of the Wnt pathway .
Triple-negative breast cancer (TNBC) refers to cancer that is negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2(HER2) and is the most aggressive subtype of breast cancer with the worst prognosis. In addition, there is also no clinically applicable therapeutic drug currently [34,35]. A drug screening study of TNBC showed that IVM could be used as a SIN3-interaction domain (SID) mimic to selectively block the interaction between SID and paired a-helix2. In addition, IVM regulated the expression of the epithelial mesenchymal-transition (EMT) related gene E-cadherin to restore the sensitivity of TNBC cells to tamoxifen, which implies the possibility that IVM functions as an epigenetic regulator in the treatment of cancer.
Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. Under the stimulation of a tumor microenvironment with a high level of adenosine triphosphate (ATP) outside tumor cells, IVM could enhance the P2 × 4/ P2 × 7/Pannexin-1 mediated release of high mobility group box-1 protein (HMGB1) . However, the release of a large amount of HMGB1 into the extracellular environment will promote immune cell-mediated immunogenic death and inflammatory reactions, which will have an inhibitory effect on the growth of tumor cells. Therefore, we believe that the anticancer effect of IVM is not limited to cytotoxicity, but also involves the regulation of the tumor microenvironment. IVM regulates the tumor microenvironment and mediates immunogenic cell death, which may be a new direction for research exploring anticancer mechanisms in the future.
2.2. Digestive system cancer
Gastric cancer is one of the most common malignant tumors worldwide. In the past year, more than one million patients with gastric cancer have been diagnosed worldwide . Nambara’s study showed that IVM could significantly inhibit the proliferation of gastric cancer cells in vivo and in vitro and that the inhibitory effect of IVM depended on the expression of Yes-associated protein 1(YAP1). The gastric cancer cell lines MKN1 and SH-10-TC have higher YAP1 expression than MKN7 and MKN28 cells, so MKN1 and SH-10-TC cells are sensitive to IVM, while MKN7 and MKN28 are not sensitive to IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment .
In a study that screened Wnt pathway inhibitors, IVM inhibited the proliferation of multiple cancers, including the colorectal cancer cell lines CC14, CC36, DLD1, and Ls174 T, and promoted apoptosis by blocking the Wnt pathway . After intervention with IVM, the expression of caspase-3 in DLD1 and Ls174 T cells increased, indicating that IVM has an apoptosis-inducing effect and inhibits the expression of the downstream genes AXIN2, LGR5, and ASCL2 in the Wnt/β-catenin pathway. However, the exact molecular target of IVM that affects the Wnt/β-catenin pathway remains to be explored.
Hepatocellular carcinoma is the fourth leading cause of cancer death worldwide. Approximately 80% of cases of liver cancer are caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection . IVM could inhibit the development of hepatocellular carcinoma by blocking YAP1 activity in spontaneous liver cancer Mob1b-/-mice .Cholangiocarcinoma is a malignant tumor that originates in the bile duct inside and outside the liver. Intuyod’s experiment found that IVM inhibited the proliferation of KKU214 cholangiocarcinoma cells in a dose- and time-dependent manner . IVM halted the cell cycle in S phase and promoted apoptosis. Surprisingly, gemcitabine-resistant KKU214 cells showed high sensitivity to IVM, which suggested that IVM shows potential for the treatment of tumors that are resistant to conventional chemotherapy drugs.
2.3. Urinary system cancer
Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. Its morbidity has increased by an average of 2% annually worldwide and the clinical treatment effect is not satisfactory [, , ]. Experiments confirmed that IVM could significantly inhibit the proliferation of five renal cell carcinoma cell lines without affecting the proliferation of normal kidney cells, and its mechanism may be related to the induction of mitochondrial dysfunction . IVM could significantly reduce the mitochondrial membrane potential and inhibit mitochondrial respiration and ATP production. The presence of the mitochondrial fuel acetyl-L-carnitine (ALCAR), and the antioxidant N-acetyl-L-cysteine (NAC), could reverse IVM-induced inhibition. In animal experiments, the immunohistochemical results for IVM-treated tumor tissues showed that the expression of the mitochondrial stress marker HEL was significantly increased, and the results were consistent with those of the cell experiments.
Prostate cancer is a malignant tumor derived from prostate epithelial cells, and its morbidity is second only to that of lung cancer among men in Western countries . In Nappi’s experiment, it was found that IVM could enhance the drug activity of the anti-androgen drug enzalutamide in the prostate cancer cell line LNCaP and reverse the resistance of the prostate cancer cell line PC3 to docetaxel . Interestingly, IVM also restored the sensitivity of the triple-negative breast cancer to the anti-estrogen drug tamoxifen , which also implies the potential for IVM to be used in endocrine therapy. Moreover, IVM was also found to have a good inhibitory effect on the prostate cancer cell line DU145 .
2.4. Hematological cancer
Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells . In an experiment designed to screen potential drugs for the treatment of leukemia, IVM preferentially killed leukemia cells at low concentrations without affecting normal hematopoietic cells . The mechanism was related to the increase in the influx of chloride ions into the cell by IVM, resulting in hyperpolarization of the plasma membrane and induction of reactive oxygen species (ROS) production. It was also proven that IVM has a synergistic effect with cytarabine and daunorubicin on the treatment of leukemia. Wang’s experiment found that IVM could selectively induce mitochondrial dysfunction and oxidative stress, causing chronic myeloid leukemia K562 cells to undergo increased caspase-dependent apoptosis compared with normal bone marrow cells . It was also confirmed that IVM inhibited tumor growth in a dose-dependent manner, and dasatinib had improved efficacy.
2.5. Reproductive system cancer
Cervical cancer is one of the most common gynecological malignancies, resulting in approximately 530,000 new cases and 270,000 deaths worldwide each year. The majority of cervical cancers are caused by human papillomavirus (HPV) infection [54,55]. IVM has been proven to significantly inhibit the proliferation and migration of HeLa cells and promote apoptosis . After intervention with IVM, the cell cycle of HeLa cells was blocked at the G1/S phase, and the cells showed typical morphological changes related to apoptosis.
Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. The 5-year survival rate after diagnosis is approximately 47% [27,57]. In a study by Hashimoto, it found that IVM inhibited the proliferation of various ovarian cancer cell lines, and the mechanism was related to the inhibition of PAK1 kinase . In research to screen potential targets for the treatment of ovarian cancer through the use of an shRNA library and a CRISPR/Cas9 library, the oncogene KPNB1 was detected. IVM could block the cell cycle and induce cell apoptosis through a KPNB1-dependent mechanism in ovarian cancer . Interestingly, IVM and paclitaxel have a synergistic effect on ovarian cancer, and combined treatment in in vivo experiments almost completely inhibited tumor growth. Furthermore, according to a report by Zhang, IVM can enhance the efficacy of cisplatin to improve the treatment of epithelial ovarian cancer, and the mechanism is related to the inhibition of the Akt/mTOR pathway .
2.6. Brain glioma
Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. Glioblastoma is the deadliest glioma, with a median survival time of only 14-17 months [61,62]. Experiments showed that IVM inhibited the proliferation of human glioblastoma U87 and T98 G cells in a dose-dependent manner and induced apoptosis in a caspase-dependent manner . This was related to the induction of mitochondrial dysfunction and oxidative stress. Moreover, IVM could induce apoptosis of human brain microvascular endothelial cells and significantly inhibit angiogenesis. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. In another study, IVM inhibited the proliferation of U251 and C6 glioma cells by inhibiting the Akt/mTOR pathway .
In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion . The DDX23 helicase activity affects the expression of miR-12 . IVM could inhibit the DDX23/miR-12 signaling pathway by affecting the activity of DDX23 helicase, thereby inhibiting malignant biological behaviors. This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. However, here, we must emphasize that because IVM cannot effectively pass the blood-brain barrier , the prospect of the use of IVM in the treatment of gliomas is not optimistic.
2.7. Respiratory system cancer
Nasopharyngeal carcinoma is a malignant tumor derived from epithelial cells of the nasopharyngeal mucosa. The incidence is obviously regional and familial, and Epstein-Barr virus (EBV) infection is closely related . In a study that screened drugs for the treatment of nasopharyngeal cancer, IVM significantly inhibited the development of nasopharyngeal carcinoma in nude mice at doses that were not toxic to normal thymocytes . In addition, IVM also had a cytotoxic effect on a variety of nasopharyngeal cancer cells in vitro, and the mechanism is related to the reduction of PAK1 kinase activity to inhibit the MAPK pathway.
Lung cancer has the highest morbidity and mortality among cancers . Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity . Nappi’s experiment also proved that IVM combined with erlotinib to achieved a synergistic killing effect by regulating EGFR activity and in HCC827 lung cancer cells . In addition, IVM could reduce the metastasis of lung cancer cells by inhibiting EMT.
Melanoma is the most common malignant skin tumor with a high mortality rate. Drugs targeting BRAF mutations such as vemurafenib, dabrafenib and PD-1 monoclonal antibodies, including pembrolizumab and nivolumab have greatly improved the prognosis of melanoma [71,72]. Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity . Interestingly, IVM could also show activity against BRAF wild-type melanoma cells, and its combination with dapafinib could significantly increase antitumor activity. Additionally, it has been confirmed that PAK1 is the key target of IVM that mediates its anti-melanoma activity, and IVM can also significantly reduce the lung metastasis of melanoma in animal experiments. Deng found that IVM could activate the nuclear translocation of TFE3 and induce autophagy-dependent cell death by dephosphorylation of TFE3 (Ser321) in SK-MEL-28 melanoma cells . However, NAC reversed the effect of IVM, which indicated that IVM increased TFE3-dependent autophagy through the ROS signaling pathway.
3. IVM-induced programmed cell death in tumor cells and related mechanisms
IVM induces different programmed cell death patterns in different tumor cells (Table 1). As shown in Table 1, the main form of IVM induced programmed cell death is apoptosis. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. The decrease in the mitochondrial membrane potential and the cytochrome c is released from mitochondria into the cytoplasm was detected after the intervention of IVM in Hela cells .Therefore, we infer that IVM induces apoptosis mainly through the mitochondrial pathway. In addition, morphological changed caused by apoptosis, including chromatin condensation, nuclear fragmentation, DNA fragmentation and apoptotic body formation were observed. Finally, IVM changed the balance between apoptosis-related proteins by upregulating the protein Bax and downregulating anti-apoptotic protein Bcl-2, thereby activating caspase-9/-3 to induce apoptosis [48,53,63] (Fig. 2 ).
Mechanisms of IVM-induced mitochondria-mediated apoptosis.
Autophagy is a lysosomal-dependent form of programmed cell death. It utilizes lysosomes to eliminate superfluous or damaged organelles in the cytoplasm to maintain homeostasis. It is characterized by double-layered or multilayered vacuolar structures containing cytoplasmic components, which are known as autophagosomes . In recent years, many studies have shown that autophagy is a double-edged sword in tumor development. On the one hand, autophagy can help tumors adapt to the nutritional deficiency of the tumor microenvironment, and to a certain extent, protect tumor cells from chemotherapy- or radiotherapy- induced injury. On the other hand, some autophagy activators can increase the sensitivity of tumors to radiotherapy and chemotherapy by inducing autophagy, and excessive activation of autophagy can also lead to tumor cell death [, , , ]. Overall, the specific environment of tumor cells will determine whether autophagy enhances or inhibits tumor development and improving autophagy activity has also become a new approach in cancer therapy. Programmed cell death mediated by autophagy after IVM intervention and the enhancement of the anticancer efficacy of IVM by regulating autophagy are interesting topics. Intervention with IVM in the breast cancer cell lines MCF-7 and MDA-MB-231 significantly increased intracellular autophagic flux and the expression of key autophagy proteins such as LC3, Bclin1, Atg5, and the formation of autophagosomes can be observed . However, after using the autophagy inhibitors chloroquine and wortmannin or knocking down Bclin1 and Atg5 by siRNA to inhibit autophagy, the anticancer activity of IVM significantly decreased. This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. In addition, researchers also used the Akt activator CA-Akt to prove that IVM mainly induces autophagy by inhibiting the phosphorylation of Akt and mTOR (Fig. 3). The phenomenon of IVM-induced autophagy has also been reported in glioma and melanoma [ 64,74]. All of the above findings indicate the potential of IVM as an autophagy activator to induce autophagy-dependent death in tumor cells.
Mechanisms of IVM-induced PAK1/Akt/mTOR-mediated autophagy.
3.3. Cross talk between IVM-induced apoptosis and autophagy
The relationship between apoptosis and autophagy is very complicated, and the cross talk between the two plays a vital role in the development of cancer . Obviously, the existing results suggest that IVM-induced apoptosis and autophagy also exhibit cross talk. For example, it was found in SK-MEL-28 melanoma cells that IVM can promote apoptosis as well as autophagy . After using the autophagy inhibitor bafilomycin A1 or siRNA to downregulate Beclin1, IVM-induced apoptosis was significantly enhanced, which suggested that enhanced autophagy will reduce IVM-induced apoptosis and that IVM-induced autophagy can protect tumor cells from apoptosis. However, in breast cancer cell experiments, it was also found that IVM could induce autophagy, and enhanced autophagy could increase the anticancer activity of IVM . The latest research shows that in normal circumstances autophagy will prevent the induction of apoptosis and apoptosis-related caspase enzyme activation will inhibit autophagy. However, in special circumstances, autophagy may also help to induce apoptosis or necrosis . In short, the relationship between IVM-induced apoptosis and autophagy involves a complex regulatory mechanism, and the specific molecular mechanism needs further study. We believe that deeper exploration of the mechanism can further guide the use of IVM in the treatment of cancer.
Pyroptosis is a type of inflammatory cell death induced by inflammasomes. The inflammasome is a multimolecular complex containing pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. PRR can identify pathogen-associated molecular patterns (PAMPs) that are structurally stable and evolutionarily conserved on the surface of pathogenic microorganisms and damage-associated molecular patterns (DAMPs) produced by damaged cells [84,85]. Inflammasomes initiate the conversion of pro-caspase-1 via self-shearing into activated caspase-1. Activated caspase-1 can cause pro-IL-1β and pro-IL-18 to mature and to be secreted. Gasdermin D(GSDMD)is a substrate for activated caspase-1 and is considered to be a key protein in the execution of pyroptosis [86,87]. In an experiment by Draganov, it was found that the release of lactate dehydrogenase (LDH) and activated caspase-1 was significantly increased in breast cancer cells after IVM intervention . In addition, characteristic pyroptosis phenomena such as cell swelling and rupturing were observed. The authors speculated that IVM may mediate the occurrence of pyroptosis via the P2 × 4/P2 × 7/NLRP3 pathway (Fig. 4), but there is no specific evidence to prove this speculation. Interestingly, in ischemia-reperfusion experiments, IVM aggravated renal ischemia via the P2 × 7/NLRP3 pathway and increased the release of proinflammatory cytokines in human proximal tubular cells . Although there is currently little evidences showing that IVM induces pyroptosis, it is important to investigate the role of IVM in inducing pyroptosis in other cancers in future studies and realize that IVM may induce different types of programmed cell death in different types of cancer.
Mechanisms of IVM-induced P2 × 4/P2 × 7/NLRP3-mediated pyroptosis.
4. Anticancer effect of IVM through other pathways
4.1. Cancer stem cells
Cancer stem cells (CSCs) are a cell population similar to stem cells with characteristics of self-renewal and differentiation potential in tumor tissue [89,90]. Although CSCs are similar to stem cells in terms of function, because of the lack of a negative feedback regulation mechanism for stem cell self-renewal, their powerful proliferation and multidirectional differentiation abilities are unrestricted, which allows CSCs to maintain certain activities during chemotherapy and radiotherapy [, , ]. When the external environment is suitable, CSCs will rapidly proliferate to reactivate the formation and growth of tumors. Therefore, CSCs have been widely recognized as the main cause of recurrence after treatment [93,94]. Guadalupe evaluated the effect of IVM on CSCs in the breast cancer cell line MDA-MB-231 . The experimental results showed that IVM would preferentially targeted and inhibited CSCs-rich cell populations compared with other cell populations in MDA-MB-231 cells. Moreover, the expression of the homeobox protein NANOG, octamer-binding protein 4 (OCT-4) and SRY-box 2 (SOX-2), which are closely related to the self-renewal and differentiation ability of stem cells in CSCs, were also significantly inhibited by IVM. This suggests that IVM may be used as a potential CSCs inhibitor for cancer therapy. Further studies showed that IVM could inhibit CSCs by regulating the PAK1-STAT3 axis .
4.2. Reversal of tumor multidrug resistance
MDR of tumor cells is the main cause of relapses and deaths after chemotherapy . ATP binding transport family-mediated drug efflux and overexpression of P-glycoprotein (P-gp) are widely considered to be the main causes of tumor MDR [, , ]. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [, , ]. In Didier’s experiments testing the effect of IVM on lymphocytic leukemia, IVM could be used as an inhibitor of P-gp to affect MDR . In Jiang’s experiment, IVM reversed the drug resistance of the vincristine-resistant colorectal cancer cell line HCT-8, doxorubicin-resistant breast cancer cell line MCF-7 and the chronic myelogenous leukemia cell line K562 . IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. Earlier, we mentioned the role of IVM in docetaxel-resistant prostate cancer  and gemcitabine-resistant cholangiocarcinoma . These results indicated the significance of applying IVM for the treatment of chemotherapy patients with MDR.
4.3. Enhanced targeted therapy and combined treatment
Targeted treatment of key mutated genes in cancer, such as EGFR in lung cancer and HER2 in breast cancer, can achieve powerful clinical effects [105,106]. HSP27 is a molecular chaperone protein that is highly expressed in many cancers and associated with drug resistance and poor prognosis. It is considered as a new target for cancer therapy . Recent studies have found that IVM could be used as an inhibitor of HSP27 phosphorylation to enhance the activity of anti-EGFR drugs in EGFR/HER2- driven tumors. An experiment found that IVM could significantly enhance the inhibitory effects of erlotinib and cetuximab on lung cancer and colorectal cancer . Earlier, we mentioned that IVM combined with conventional chemotherapeutic drugs such as cisplatin , paclitaxel , daunorubicin and cytarabine , or with targeted drugs such as dasatinib  and dapafenib  shows great potential for cancer treatment. The combination of drugs can effectively increase efficacy, reduce toxicity or delay drug resistance. Therefore, combination therapy is the most common method of chemotherapy. IVM has a variety of different mechanisms of action in different cancers, and its potential for synergistic effects and enhanced efficacy in combination therapy was of particular interest to us. Not only does IVM not overlap with other therapies in term of its mechanism of action, but the fact that of IVM has multiple targets suggests that it is not easy to produce IVM resistance. Therefore, continued study and testing of safe and effective combination drug therapies is essential to maximize the anticancer effects of IVM.
5. Molecular targets and signaling pathways involved in the anticancer potential of IVM
As mentioned above, the anticancer mechanism of IVM involves a wide range of signaling pathways such as Wnt/β-catenin, Akt/mTOR, MAPK and other possible targets such as PAK1 and HSP27, as well as other mechanisms of action (Table 2 ). We found that IVM inhibits tumor cell development in a PAK1-dependent manner in most cancers. Consequently, we have concentrated on discussing the role of PAK1 kinase and cross-talk between various pathways and PAK1 to provide new perspectives on the mechanism of IVM function.
As a member of the PAK family of serine/threonine kinases, PAK1 has a multitude of biological functions such as regulating cell proliferation and apoptosis, cell movement, cytoskeletal dynamics and transformation . Previous studies have indicated that PAK1 is located at the intersection of multiple signaling pathways related to tumorigenesis and is a key regulator of cancer signaling networks (Fig. 5). The excessive activation of PAK1 is involved in the formation, development, and invasion of various cancers [ 109,110]. Targeting PAK1 is a novel and promising method for cancer treatment, and the development of PAK1 inhibitors has attracted widespread attention . IVM is a PAK1 inhibitor in a variety of tumors, and it has good safety compared to that of other PAK1 inhibitors such as IPA-3. In melanoma and nasopharyngeal carcinoma, IVM inhibited cell proliferation activity by inhibiting PAK1 to downregulate the expression of MEK 1/2 and ERK1/2 [69,73]. After IVM intervention in breast cancer, the expression of PAK1 was also significantly inhibited, and the use of siRNA to downregulate the expression of PAK1 in tumor cells significantly reduced the anticancer activity of IVM. Interestingly, IVM could inhibit the expression of PAK1 protein but did not affect the expression of PAK1 mRNA .The proteasome inhibitor MG132 reversed the suppressive effect of IVM, which indicated that IVM mainly degraded PAK1 via the proteasome ubiquitination pathway. We have already mentioned that IVM plays an anticancer role in various tumors by regulating pathways closely related to cancer development. PAK1 is at the junction of these pathways. Overall, we speculate that IVM can regulate the Akt/mTOR, MAPK and other pathways that are essential for tumor cell proliferation by inhibiting PAK1 expression, which plays an anticancer role in most cancers.
Malignant tumors are one of the most serious diseases that threaten human health and social development today, and chemotherapy is one of the most important methods for the treatment of malignant tumors. In recent years, many new chemotherapeutic drugs have entered the clinic, but tumor cells are prone to drug resistance and obvious adverse reactions to these drugs. Therefore, the development of new drugs that can overcome resistance, improve anticancer activity, and reduce side effects is an urgent problem to be solved in chemotherapy. Drug repositioning is a shortcut to accelerate the development of anticancer drugs.
As mentioned above, the broad-spectrum antiparasitic drug IVM, which is widely used in the field of parasitic control, has many advantages that suggest that it is worth developing as a potential new anticancer drug. IVM selectively inhibits the proliferation of tumors at a dose that is not toxic to normal cells and can reverse the MDR of tumors. Importantly, IVM is an established drug used for the treatment of parasitic diseases such as river blindness and elephantiasis. It has been widely used in humans for many years, and its various pharmacological properties, including long- and short-term toxicological effects and drug metabolism characteristics are very clear. In healthy volunteers, the dose was increased to 2 mg/Kg, and no serious adverse reactions were found, while tests in animals such as mice, rats, and rabbits found that the median lethal dose (LD50) of IVM was 10-50 mg/Kg  In addition, IVM has also been proven to show good permeability in tumor tissues . Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug. There are still some problems that need to be studied and resolved before IVM is used in the clinic.
(1) Although a large number of research results indicate that IVM affects multiple signaling pathways in tumor cells and inhibits proliferation, IVM may cause antitumor activity in tumor cells through specific targets. However, to date, no exact target for IVM action has been found. (2) IVM regulates the tumor microenvironment, inhibits the activity of tumor stem cells and reduces tumor angiogenesis and tumor metastasis. However, there is no systematic and clear conclusion regarding the related molecular mechanism. Therefore, in future research, it is necessary to continue to explore the specific mechanism of IVM involved in regulating the tumor microenvironment, angiogenesis and EMT. (3) It has become increasingly clear that IVM can induce a mixed cell death mode involving apoptosis, autophagy and pyroptosis depending on the cell conditions and cancer type. Identifying the predominant or most important contributor to cell death in each cancer type and environment will be crucial in determining the effectiveness of IVM-based treatments. (4) IVM can enhance the sensitivity of chemotherapeutic drugs and reduce the production of resistance. Therefore, IVM should be used in combination with other drugs to achieve the best effect, while the specific medication plan used to combine IVM with other drugs remains to be explored.
Most of the anticancer research performed on the avermectin family has been focused on avermectin and IVM until now. Avermectin family drugs such as selamectin [36,41,113], and doramectin  also have anticancer effects, as previously reported. With the development of derivatives of the avermectin family that are more efficient and less toxic, relevant research on the anticancer mechanism of the derivatives still has great value. Existing research is sufficient to demonstrate the great potential of IVM and its prospects as a novel promising anticancer drug after additional research. We believe that IVM can be further developed and introduced clinically as part of new cancer treatments in the near future.
Declaration of Competing Interest
The authors report no declarations of interest.
This work was supported by the Science Research Innovation Team Project of Anhui Colleges and Universities (2016-40), the Bengbu City Natural Science Foundation (2019-12), the Key Projects of Science Research of Bengbu Medical College (BYKY2019009ZD) and National University Students’ Innovation and Entrepreneurship Training Program (201910367001).
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company’s public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre – including this research content – immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
This article has been cited by other articles in PMC.
1. Campbell W.C., Fisher M.H., Stapley E.O., Albers-Schonberg G., Jacob T.A. Ivermectin: a potent new antiparasitic agent. Science. 1983;221(4613):823–828. doi: 10.1126/science.6308762. [PubMed] [CrossRef] [Google Scholar]
2. Prichard R.K., Geary T.G. Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. Int J Parasitol Drugs Drug Resist. 2019;10:69–83. doi: 10.1016/j.ijpddr.2019.06.002.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
3. Ashour D.S. Ivermectin: From theory to clinical application. Int J Antimicrob Agents. 2019;54(2):134–142. doi: 10.1016/j.ijantimicag.2019.05.003.[PubMed] [CrossRef] [Google Scholar]
7. Crump A. Ivermectin: enigmatic multifaceted’ wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo) 2017;70(5):495–505. doi: 10.1038/ja.2017.11. [PubMed] [CrossRef] [Google Scholar]
8. McKerrow J.H. Recognition of the role of Natural Products as drugs to treat neglected tropical diseases by the 2015 Nobel prize in physiology or medicine. Nat Prod Rep. 2015;32(12):1610–1611. doi: 10.1039/c5np90043c. [PubMed] [CrossRef] [Google Scholar]
9. Kane N.S., Hirschberg B., Qian S., Hunt D., Thomas B., Brochu R., Ludmerer S.W., Zheng Y., Smith M., Arena J.P., Cohen C.J., Schmatz D., Warmke J., Cully D.F. Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proc Natl Acad Sci U S A. 2000;97(25):13949–13954. doi: 10.1073/pnas.240464697.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
10. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Proc Natl Acad Sci U S A. 1979;76(4):2062–2066. doi: 10.1073/pnas.76.4.2062. [PMC free article][PubMed] [CrossRef] [Google Scholar]
11. Smit M.R., Ochomo E.O., Aljayyoussi G., Kwambai T.K., Abong’o B.O., Chen T., Bousema T., Slater H.C., Waterhouse D., Bayoh N.M., Gimnig J.E., Samuels A.M., Desai M.R., Phillips-Howard P.A., Kariuki S.K., Wang D., Ward S.A., Ter Kuile F.O. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(6):615–626. doi: 10.1016/s1473-3099(18)30163-4. [PubMed] [CrossRef] [Google Scholar]
12. Foy B.D., Alout H., Seaman J.A., Rao S., Magalhaes T., Wade M., Parikh S., Soma D.D., Sagna A.B., Fournet F., Slater H.C., Bougma R., Drabo F., Diabate A., Coulidiaty A.G.V., Rouamba N., Dabire R.K. Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial. Lancet. 2019;393(10180):1517–1526. doi: 10.1016/s0140-6736(18)32321-3.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
13. Udensi U.K., Fagbenro-Beyioku A.F. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. J Vector Borne Dis. 2012;49(3):143–150.[PubMed] [Google Scholar]
14. Katz N., Araujo N., Coelho P.M.Z., Morel C.M., Linde-Arias A.R., Yamada T., Horimatsu Y., Suzuki K., Sunazuka T., Omura S. Ivermectin efficacy against Biomphalaria, intermediate host snail vectors of Schistosomiasis. J Antibiot (Tokyo) 2017;70(5):680–684. doi: 10.1038/ja.2017.31.[PubMed] [CrossRef] [Google Scholar]
15. B. MM, E.-S. AA Therapeutic potential of myrrh and ivermectin against experimental Trichinella spiralis infection in mice. The Korean journal of parasitology. 2013;51(3):297–304. doi: 10.3347/kjp.2013.51.3.297.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
16. Hanafi H.A., Szumlas D.E., Fryauff D.J., El-Hossary S.S., Singer G.A., Osman S.G., Watany N., Furman B.D., Hoel D.F. Effects of ivermectin on blood-feeding Phlebotomus papatasi, and the promastigote stage of Leishmania major. Vector Borne Zoonotic Dis. 2011;11(1):43–52. doi: 10.1089/vbz.2009.0030. [PubMed] [CrossRef] [Google Scholar]
17. Mastrangelo E., Pezzullo M., De Burghgraeve T., Kaptein S., Pastorino B., Dallmeier K., de Lamballerie X., Neyts J., Hanson A.M., Frick D.N., Bolognesi M., Milani M. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012;67(8):1884–1894. doi: 10.1093/jac/dks147. [PMC free article][PubMed] [CrossRef] [Google Scholar]
18. Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851–856. doi: 10.1042/bj20120150. [PMC free article][PubMed] [CrossRef] [Google Scholar]
19. Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020:104787. doi: 10.1016/j.antiviral.2020.104787.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Yan S., Ci X., Chen N., Chen C., Li X., Chu X., Li J., Deng X. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res. 2011;60(6):589–596. doi: 10.1007/s00011-011-0307-8.[PubMed] [CrossRef] [Google Scholar]
21. Franklin K.M., Asatryan L., Jakowec M.W., Trudell J.R., Bell R.L., Davies D.L. P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders. Front Neurosci. 2014;8:176. doi: 10.3389/fnins.2014.00176.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. Anticancer Drugs. 1996;7(7):745–751. doi: 10.1097/00001813-199609000-00005. [PubMed] [CrossRef] [Google Scholar]
23. Markowska A., Kaysiewicz J., Markowska J., Huczynski A. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. Bioorg Med Chem Lett. 2019;29(13):1549–1554. doi: 10.1016/j.bmcl.2019.04.045. [PubMed] [CrossRef] [Google Scholar]
24. Juarez M., Schcolnik-Cabrera A., Duenas-Gonzalez A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018;8(2):317–331. [PMC free article][PubMed] [Google Scholar]
25. Liu J., Zhang K., Cheng L., Zhu H., Xu T. Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin. Drug Des Devel Ther. 2020;14:285–296. doi: 10.2147/dddt.S237393.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
26. Antoszczak M., Markowska A., Markowska J., Huczynski A. Old wine in new bottles: Drug repurposing in oncology. Eur J Pharmacol. 2020;866:172784. doi: 10.1016/j.ejphar.2019.172784. [PubMed] [CrossRef] [Google Scholar]
27. Kobayashi Y., Banno K., Kunitomi H., Tominaga E., Aoki D. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. J Gynecol Oncol. 2019;30(1):e10. doi: 10.3802/jgo.2019.30.e10.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
28. Yoshida G.J. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10(1):67. doi: 10.1186/s13045-017-0436-9.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
29. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. Drug Discov Today. 2016;21(1):190–199. doi: 10.1016/j.drudis.2015.09.017. [PubMed] [CrossRef] [Google Scholar]
30. Harbeck N., Penault-Llorca F., Cortes J., Gnant M., Houssami N., Poortmans P., Ruddy K., Tsang J., Cardoso F. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66. doi: 10.1038/s41572-019-0111-2. [PubMed] [CrossRef] [Google Scholar]
31. Ginsburg O., Bray F., Coleman M.P., Vanderpuye V., Eniu A., Kotha S.R., Sarker M., Huong T.T., Allemani C., Dvaladze A., Gralow J., Yeates K., Taylor C., Oomman N., Krishnan S., Sullivan R., Kombe D., Blas M.M., Parham G., Kassami N., Conteh L. The global burden of women’s cancers: a grand challenge in global health. Lancet. 2017;389(10071):847–860. doi: 10.1016/s0140-6736(16)31392-7.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
32. Dou Q., Chen H.N., Wang K., Yuan K., Lei Y., Li K., Lan J., Chen Y., Huang Z., Xie N., Zhang L., Xiang R., Nice E.C., Wei Y., Huang C. Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer. Cancer Res. 2016;76(15):4457–4469. doi: 10.1158/0008-5472.CAN-15-2887.[PubMed] [CrossRef] [Google Scholar]
33. Diao H., Cheng N., Zhao Y., Xu H., Dong H., Thamm D.H., Zhang D., Lin D. Ivermectin inhibits canine mammary tumor growth by regulating cell cycle progression and WNT signaling. BMC Vet Res. 2019;15(1):276. doi: 10.1186/s12917-019-2026-2.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. Diana A., Carlino F., Franzese E., Oikonomidou O., Criscitiello C., De Vita F., Ciardiello F., Orditura M. Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes. Cancers (Basel) 2020;12(4) doi: 10.3390/cancers12040819.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. Deepak K.G.K., Vempati R., Nagaraju G.P., Dasari V.R., N. S, Rao D.N., Malla R.R. Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol Res. 2020;153:104683. doi: 10.1016/j.phrs.2020.104683. [PubMed] [CrossRef] [Google Scholar]
36. Kwon Y.J., Petrie K., Leibovitch B.A., Zeng L., Mezei M., Howell L., Gil V., Christova R., Bansal N., Yang S., Sharma R., Ariztia E.V., Frankum J., Brough R., Sbirkov Y., Ashworth A., Lord C.J., Zelent A., Farias E., Zhou M.M., Waxman S. Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. Mol Cancer Ther. 2015;14(8):1824–1836. doi: 10.1158/1535-7163.MCT-14-0980-T.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Draganov D., Gopalakrishna-Pillai S., Chen Y.R., Zuckerman N., Moeller S., Wang C., Ann D., Lee P.P. Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci Rep. 2015;5:16222. doi: 10.1038/srep16222. [PMC free article][PubMed] [CrossRef] [Google Scholar]
38. Thanh Huong P., Gurshaney S., Thanh Binh N., Gia Pham A., Hoang Nguyen H., Thanh Nguyen X., Pham-The H., Tran P.T., Truong Vu K., Xuan Duong N., Pelucchi C., La Vecchia C., Boffetta P., Nguyen H.D., Luu H.N. Emerging Role of Circulating Tumor Cells in Gastric Cancer. Cancers (Basel) 2020;12(3) doi: 10.3390/cancers12030695.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
39. Nambara S., Masuda T., Nishio M., Kuramitsu S., Tobo T., Ogawa Y., Hu Q., Iguchi T., Kuroda Y., Ito S., Eguchi H., Sugimachi K., Saeki H., Oki E., Maehara Y., Suzuki A., Mimori K. Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer. Oncotarget. 2017;8(64):107666–107677. doi: 10.18632/oncotarget.22587.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Zanconato F., Cordenonsi M., Piccolo S. YAP and TAZ: a signalling hub of the tumour microenvironment. Nat Rev Cancer. 2019;19(8):454–464. doi: 10.1038/s41568-019-0168-y. [PubMed] [CrossRef] [Google Scholar]
41. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med. 2014;6(10):1263–1278. doi: 10.15252/emmm.201404084.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
42. Yang J.D., Hainaut P., Gores G.J., Amadou A., Plymoth A., Roberts L.R. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604. doi: 10.1038/s41575-019-0186-y.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
43. Nishio M., Sugimachi K., Goto H., Wang J., Morikawa T., Miyachi Y., Takano Y., Hikasa H., Itoh T., Suzuki S.O., Kurihara H., Aishima S., Leask A., Sasaki T., Nakano T., Nishina H., Nishikawa Y., Sekido Y., Nakao K., Shin-Ya K., Mimori K., Suzuki A. Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc Natl Acad Sci U S A. 2016;113(1):71–80. doi: 10.1073/pnas.1517188113.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Intuyod K., Hahnvajanawong C., Pinlaor P., Pinlaor S. Anti-parasitic Drug Ivermectin Exhibits Potent Anticancer Activity Against Gemcitabine-resistant Cholangiocarcinoma In Vitro. Anticancer Res. 2019;39(9):4837–4843. doi: 10.21873/anticanres.13669. [PubMed] [CrossRef] [Google Scholar]
45. Wang Y., Su J., Wang Y., Fu D., Ideozu J.E., Geng H., Cui Q., Wang C., Chen R., Yu Y., Niu Y., Yue D. The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1-SPP1- NF-kappaB signaling axis. J Exp Clin Cancer Res. 2019;38(1):386. doi: 10.1186/s13046-019-1347-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
46. Xu W.H., Shi S.N., Xu Y., Wang J., Wang H.K., Cao D.L., Shi G.H., Qu Y.Y., Zhang H.L., Ye D.W. Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma. J Transl Med. 2019;17(1):363. doi: 10.1186/s12967-019-2113-y.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
47. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. doi: 10.3322/caac.21551.[PubMed] [CrossRef] [Google Scholar]
48. Zhu M., Li Y., Zhou Z. Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. Biochemical and Biophysical Research Communications. 2017;492(3):373–378. doi: 10.1016/j.bbrc.2017.08.097. [PubMed] [CrossRef] [Google Scholar]
50. Nappi L., Aguda A.H., Nakouzi N.A., Lelj-Garolla B., Beraldi E., Lallous N., Thi M., Moore S., Fazli L., Battsogt D., Stief S., Ban F., Nguyen N.T., Saxena N., Dueva E., Zhang F., Yamazaki T., Zoubeidi A., Cherkasov A., Brayer G.D., Gleave M. Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models. J Clin Invest. 2020;130(2):699–714. doi: 10.1172/jci130819.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
51. Sharmeen S., Skrtic M., Sukhai M.A., Hurren R., Gronda M., Wang X., Fonseca S.B., Sun H., Wood T.E., Ward R., Minden M.D., Batey R.A., Datti A., Wrana J., Kelley S.O., Schimmer A.D. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010;116(18):3593–3603. doi: 10.1182/blood-2010-01-262675.[PubMed] [CrossRef] [Google Scholar]
53. Wang J., Xu Y., Wan H., Hu J. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2018;497(1):241–247. doi: 10.1016/j.bbrc.2018.02.063. [PubMed] [CrossRef] [Google Scholar]
54. Dong Z., Yu C., Rezhiya K., Gulijiahan A., Wang X. Downregulation of miR-146a promotes tumorigenesis of cervical cancer stem cells via VEGF/CDC42/PAK1 signaling pathway. Artif Cells Nanomed Biotechnol. 2019;47(1):3711–3719. doi: 10.1080/21691401.2019.1664560.[PubMed] [CrossRef] [Google Scholar]
55. Carneiro S.R., da Silva Lima A.A., de Fatima Silva Santos G., de Oliveira C.S.B., Almeida M.C.V., da Conceicao Nascimento Pinheiro M. Relationship between Oxidative Stress and Physical Activity in Women with Squamous Intraepithelial Lesions in a Cervical Cancer Control Program in the Brazilian Amazon. Oxid Med Cell Longev. 2019;2019doi: 10.1155/2019/8909852. [PMC free article][PubMed] [CrossRef] [Google Scholar]
56. Zhang P., Zhang Y., Liu K., Liu B., Xu W., Gao J., Ding L., Tao L. Ivermectin induces cell cycle arrest and apoptosis of HeLa cells via mitochondrial pathway. Cell Prolif. 2019;52(2):e12543. doi: 10.1111/cpr.12543.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
57. Moufarrij S., Dandapani M., Arthofer E., Gomez S., Srivastava A., Lopez-Acevedo M., Villagra A., Chiappinelli K.B. Epigenetic therapy for ovarian cancer: promise and progress. Clin Epigenetics. 2019;11(1):7. doi: 10.1186/s13148-018-0602-0.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Hashimoto H., Messerli S.M., Sudo T., Maruta H. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009;3(6):243–246.[PubMed] [Google Scholar]
59. Kodama M., Kodama T., Newberg J.Y., Katayama H., Kobayashi M., Hanash S.M., Yoshihara K., Wei Z., Tien J.C., Rangel R., Hashimoto K., Mabuchi S., Sawada K., Kimura T., Copeland N.G., Jenkins N.A. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2017;114(35):E7301–E7310. doi: 10.1073/pnas.1705441114.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
60. Zhang X., Qin T., Zhu Z., Hong F., Xu Y., Zhang X., Xu X., Ma A. Ivermectin Augments the In Vitro and In Vivo Efficacy of Cisplatin in Epithelial Ovarian Cancer by Suppressing Akt/mTOR Signaling. Am J Med Sci. 2020;359(2):123–129. doi: 10.1016/j.amjms.2019.11.001. [PubMed] [CrossRef] [Google Scholar]
61. Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15(7):405–417. doi: 10.1038/s41582-019-0220-2.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Wen P.Y., Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507. doi: 10.1056/NEJMra0708126. [PubMed] [CrossRef] [Google Scholar]
63. Liu Y., Fang S., Sun Q., Liu B. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2016;480(3):415–421. doi: 10.1016/j.bbrc.2016.10.064. [PubMed] [CrossRef] [Google Scholar]
64. Liu J., Liang H., Chen C., Wang X., Qu F., Wang H., Yang K., Wang Q., Zhao N., Meng J., Gao A. Ivermectin induces autophagy-mediated cell death through the AKT/mTOR signaling pathway in glioma cells. Biosci Rep. 2019;39(12) doi: 10.1042/bsr20192489.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
65. Kwak H.J., Kim Y.J., Chun K.R., Woo Y.M., Park S.J., Jeong J.A., Jo S.H., Kim T.H., Min H.S., Chae J.S., Choi E.J., Kim G., Shin S.H., Gwak H.S., Kim S.K., Hong E.K., Lee G.K., Choi K.H., Kim J.H., Yoo H., Park J.B., Lee S.H. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene. 2011;30(21):2433–2442. doi: 10.1038/onc.2010.620. [PubMed] [CrossRef] [Google Scholar]
66. Yin J., Park G., Lee J.E., Choi E.Y., Park J.Y., Kim T.H., Park N., Jin X., Jung J.E., Shin D., Hong J.H., Kim H., Yoo H., Lee S.H., Kim Y.J., Park J.B., Kim J.H. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain. 2015;138(Pt 9):2553–2570. doi: 10.1093/brain/awv167. [PubMed] [CrossRef] [Google Scholar]
67. Kircik L.H., Del Rosso J.Q., Layton A.M., Schauber J. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. J Drugs Dermatol. 2016;15(3):325–332. [PubMed] [Google Scholar]
68. Chen Y.P., Chan A.T.C., Le Q.T., Blanchard P., Sun Y., Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64–80. doi: 10.1016/s0140-6736(19)30956-0.[PubMed] [CrossRef] [Google Scholar]
69. Gallardo F., Mariamé B., Gence R., Tilkin-Mariamé A.-F. Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth. Drug Design, Development and Therapy. 2018;12:2805–2814. doi: 10.2147/dddt.S172538. [PMC free article][PubMed] [CrossRef] [Google Scholar]
70. Thawani R., McLane M., Beig N., Ghose S., Prasanna P., Velcheti V., Madabhushi A. Radiomics and radiogenomics in lung cancer: A review for the clinician. Lung Cancer. 2018;115:34–41. doi: 10.1016/j.lungcan.2017.10.015. [PubMed] [CrossRef] [Google Scholar]
71. Patel H., Yacoub N., Mishra R., White A., Long Y., Alanazi S., Garrett J.T. Current Advances in the Treatment of BRAF-Mutant Melanoma. Cancers (Basel) 2020;12(2) doi: 10.3390/cancers12020482.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
72. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma. Eur J Cancer. 2019;123:58–71. doi: 10.1016/j.ejca.2019.08.032. [PubMed] [CrossRef] [Google Scholar]
73. Gallardo F., Teiti I., Rochaix P., Demilly E., Jullien D., Mariamé B., Tilkin-Mariamé A.-F. Macrocyclic Lactones Block Melanoma Growth, Metastases Development and Potentiate Activity of Anti– BRAF V600 Inhibitors. Clinical Skin Cancer. 2016;1(1):4–14. doi: 10.1016/j.clsc.2016.05.001. e3. [CrossRef] [Google Scholar]
74. Deng F., Xu Q., Long J., Xie H. Suppressing ROS‐TFE3‐dependent autophagy enhances ivermectin‐induced apoptosis in human melanoma cells. Journal of Cellular Biochemistry. 2018;120(2):1702–1715. doi: 10.1002/jcb.27490. [PubMed] [CrossRef] [Google Scholar]
75. Nagata S. Apoptosis and Clearance of Apoptotic Cells. Annu Rev Immunol. 2018;36:489–517. doi: 10.1146/annurev-immunol-042617-053010. [PubMed] [CrossRef] [Google Scholar]
76. Degterev A., Yuan J. Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol. 2008;9(5):378–390. doi: 10.1038/nrm2393. [PubMed] [CrossRef] [Google Scholar]
79. Gewirtz D.A. The four faces of autophagy: implications for cancer therapy. Cancer Res. 2014;74(3):647–651. doi: 10.1158/0008-5472.Can-13-2966. [PubMed] [CrossRef] [Google Scholar]
80. Galluzzi L., Pietrocola F., Bravo-San Pedro J.M., Amaravadi R.K., Baehrecke E.H., Cecconi F., Codogno P., Debnath J., Gewirtz D.A., Karantza V., Kimmelman A., Kumar S., Levine B., Maiuri M.C., Martin S.J., Penninger J., Piacentini M., Rubinsztein D.C., Simon H.U., Simonsen A., Thorburn A.M., Velasco G., Ryan K.M., Kroemer G. Autophagy in malignant transformation and cancer progression. Embo j. 2015;34(7):856–880. doi: 10.15252/embj.201490784.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
81. Galluzzi L., Bravo-San Pedro J.M., Demaria S., Formenti S.C., Kroemer G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol. 2017;14(4):247–258. doi: 10.1038/nrclinonc.2016.183.[PubMed] [CrossRef] [Google Scholar]
82. Ravegnini G., Sammarini G., Nannini M., Pantaleo M.A., Biasco G., Hrelia P., Angelini S. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis. Autophagy. 2017;13(3):452–463. doi: 10.1080/15548627.2016.1256522.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
83. Marino G., Niso-Santano M., Baehrecke E.H., Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81–94. doi: 10.1038/nrm3735. [PMC free article][PubMed] [CrossRef] [Google Scholar]
84. Fang Y., Tian S., Pan Y., Li W., Wang Q., Tang Y., Yu T., Wu X., Shi Y., Ma P., Shu Y. Pyroptosis: A new frontier in cancer. Biomed Pharmacother. 2020;121:109595. doi: 10.1016/j.biopha.2019.109595. [PubMed] [CrossRef] [Google Scholar]
85. Gong T., Liu L., Jiang W., Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020;20(2):95–112. doi: 10.1038/s41577-019-0215-7. [PubMed] [CrossRef] [Google Scholar]
86. Liu X., Zhang Z., Ruan J., Pan Y., Magupalli V.G., Wu H., Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–158. doi: 10.1038/nature18629. [PMC free article][PubMed] [CrossRef] [Google Scholar]
88. Han S.J., Lovaszi M., Kim M., D’Agati V., Hasko G., Lee H.T. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. Faseb j. 2020;34(4):5465–5482. doi: 10.1096/fj.201903287R. [PMC free article][PubMed] [CrossRef] [Google Scholar]
89. O’Brien C.A., Kreso A., Jamieson C.H. Cancer stem cells and self-renewal. Clin Cancer Res. 2010;16(12):3113–3120. doi: 10.1158/1078-0432.CCR-09-2824.[PubMed] [CrossRef] [Google Scholar]
90. Huang Z., Wu T., Liu A.Y., Ouyang G. Differentiation and transdifferentiation potentials of cancer stem cells. Oncotarget. 2015;6(37):39550–39563. doi: 10.18632/oncotarget.6098.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
91. Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., Dewhirst M.W., Bigner D.D., Rich J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–760. doi: 10.1038/nature05236. [PubMed] [CrossRef] [Google Scholar]
92. Dean M., Fojo T., Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–284. doi: 10.1038/nrc1590.[PubMed] [CrossRef] [Google Scholar]
93. Li X., Lewis M.T., Huang J., Gutierrez C., Osborne C.K., Wu M.F., Hilsenbeck S.G., Pavlick A., Zhang X., Chamness G.C., Wong H., Rosen J., Chang J.C. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672–679. doi: 10.1093/jnci/djn123. [PubMed] [CrossRef] [Google Scholar]
94. Diehn M., Clarke M.F. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. J Natl Cancer Inst. 2006;98(24):1755–1757. doi: 10.1093/jnci/djj505. [PubMed] [CrossRef] [Google Scholar]
95. Dominguez-Gomez G., Chavez-Blanco A., Medina-Franco J.L., Saldivar-Gonzalez F., Flores-Torrontegui Y., Juarez M., Diaz-Chavez J., Gonzalez-Fierro A., Duenas-Gonzalez A. Ivermectin as an inhibitor of cancer stemlike cells. Mol Med Rep. 2018;17(2):3397–3403. doi: 10.3892/mmr.2017.8231. [PubMed] [CrossRef] [Google Scholar]
96. Kim J.H., Choi H.S., Kim S.L., Lee D.S. The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation. Cancers (Basel) 2019;11(10) doi: 10.3390/cancers11101527.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
97. Wang J., Seebacher N., Shi H., Kan Q., Duan Z. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. Oncotarget. 2017;8(48):84559–84571. doi: 10.18632/oncotarget.19187.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
98. Niazi M., Zakeri-Milani P., Najafi Hajivar S., Soleymani Goloujeh M., Ghobakhlou N., Shahbazi Mojarrad J., Valizadeh H. Nano-based strategies to overcome p-glycoprotein-mediated drug resistance. Expert Opin Drug Metab Toxicol. 2016;12(9):1021–1033. doi: 10.1080/17425255.2016.1196186.[PubMed] [CrossRef] [Google Scholar]
100. Kibria G., Hatakeyama H., Harashima H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res. 2014;37(1):4–15. doi: 10.1007/s12272-013-0276-2. [PubMed] [CrossRef] [Google Scholar]
101. Lespine A., Dupuy J., Orlowski S., Nagy T., Glavinas H., Krajcsi P., Alvinerie M. Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3) Chem Biol Interact. 2006;159(3):169–179. doi: 10.1016/j.cbi.2005.11.002. [PubMed] [CrossRef] [Google Scholar]
102. Pouliot J.F., L’Heureux F., Liu Z., Prichard R.K., Georges E. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Biochem Pharmacol. 1997;53(1):17–25. doi: 10.1016/s0006-2952(96)00656-9. [PubMed] [CrossRef] [Google Scholar]
103. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. Eur J Pharm Sci. 2007;30(1):84–94. doi: 10.1016/j.ejps.2006.10.004. [PubMed] [CrossRef] [Google Scholar]
104. Jiang L., Wang P., Sun Y.J., Wu Y.J. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. J Exp Clin Cancer Res. 2019;38(1):265. doi: 10.1186/s13046-019-1251-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
105. Loibl S., Gianni L. HER2-positive breast cancer. Lancet. 2017;389(10087):2415–2429. doi: 10.1016/s0140-6736(16)32417-5.[PubMed] [CrossRef] [Google Scholar]
106. Lim S.M., Syn N.L., Cho B.C., Soo R.A. Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies. Cancer Treat Rev. 2018;65:1–10. doi: 10.1016/j.ctrv.2018.02.006.[PubMed] [CrossRef] [Google Scholar]
107. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment? Cancers (Basel) 2019;11(8) doi: 10.3390/cancers11081195.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
108. Kumar R., Gururaj A.E., Barnes C.J. p21-activated kinases in cancer. Nat Rev Cancer. 2006;6(6):459–471. doi: 10.1038/nrc1892.[PubMed] [CrossRef] [Google Scholar]
109. Rane C.K., Minden A. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2019;54:40–49. doi: 10.1016/j.semcancer.2018.01.006.[PubMed] [CrossRef] [Google Scholar]
110. Dammann K., Khare V., Gasche C. Tracing PAKs from GI inflammation to cancer. Gut. 2014;63(7):1173–1184. doi: 10.1136/gutjnl-2014-306768. [PubMed] [CrossRef] [Google Scholar]
111. Kumar R., Li D.Q. PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Adv Cancer Res. 2016;130:137–209. doi: 10.1016/bs.acr.2016.01.002. [PubMed] [CrossRef] [Google Scholar]
112. Guzzo C.A., Furtek C.I., Porras A.G., Chen C., Tipping R., Clineschmidt C.M., Sciberras D.G., Hsieh J.Y., Lasseter K.C. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122–1133. doi: 10.1177/009127002401382731. [PubMed] [CrossRef] [Google Scholar]
113. Geyer J., Gavrilova O., Petzinger E. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice. J Vet Pharmacol Ther. 2009;32(1):87–96. doi: 10.1111/j.1365-2885.2008.01007.x. [PubMed] [CrossRef] [Google Scholar]
114. Gao A., Wang X., Xiang W., Liang H., Gao J., Yan Y. Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin. J Pharm Pharmacol. 2010;62(3):393–399. doi: 10.1211/jpp.62.03.0016. [PubMed] [CrossRef] [Google Scholar]
A 33-fold spike has been witnessed in the occurrence of a blood clot in the lung, which can be fatal, in 30 days after getting infected with coronavirus, found a new study.
Another five-fold rise in the risk of getting deep vein thrombosis (DVT) has been linked with contracting Covid, it also said.
The findings of the research were published in the British Medical Journal on Thursday.
The study was carried out by Anne-Marie Fors Connolly of Umeå University in Sweden and her colleagues. The team looked to check the risk of DVT, pulmonary embolism, which is a blood clot in the lung, and other types of bleeding in over one million people, who were also the confirmed cases of Covid.
They also found a two-fold hike in the risk of bleeding after 30 days of the infection.
After becoming infected with coronavirus, patients remain at heightened risk of pulmonary embolism for six months. For bleeding and DVT, the risk is for two and three months, respectively.
“Pulmonary embolism can be fatal, so it is important to be aware [of this risk]. If you suddenly find yourself short of breath, and it doesn’t pass, [and] you’ve been infected with the coronavirus, then it might be an idea to seek help, because we find this increased risk for up to six months,” Connolly told the Guardian.
The World Health Organization’s international pandemic treaty signals the organization may be planning to seize power over health systems and push the world toward universal health coverage.
The globalist cabal is planning to monopolize health systems worldwide through the creation of an international pandemic treaty that makes the World Health Organization (WHO) the sole decision maker on pandemic matters.
The WHO may also be planning to seize power over health systems more broadly. Tedros Adhanom Ghebreyesus has stated that his “central priority” as director-general of the WHO is to push the world toward universal health coverage.
In the name of keeping everyone “safe” from infection, the globalist cabal has justified unprecedented attacks on democracy, civil liberties and personal freedoms, including the right to choose your own medical treatment.
Now, the WHO is gearing up to make its pandemic leadership permanent, and to extend it into the health care systems of every nation. The idea is to implement universal health care organized by the WHO as part of the Great Reset.
If this treaty goes through, the WHO would have the power to call for mandatory vaccinations and health passports, and its decision would supersede national and state laws.
Considering the WHO changed its definition of “pandemic” to “a worldwide epidemic of a disease,” removing the requirement of high morbidity, just about anything could be made to fit the pandemic criterion, including obesity.
The SMART Health Cards system is used by more than a dozen countries, 25 U.S. states, Puerto Rico and Washington, D.C.; the Australian Parliament is pushing a “Trusted Digital Identity Bill”; U.S. Congress is pushing the “Improving Digital Identity Act” and the WHO has signed a deal with a Deutsche Telekom subsidiary to build the first global digital vaccine passport.
All of these have one thing in common: the end goal, which is to expand them into a souped-up, global social credit system.
A new peer-reviewed study shows more than two-thirds of adolescents with COVID-19 vaccine-related myopericarditis had persistent heart abnormalities months after their initial diagnosis, raising concerns for potential long-term effects and contradicting claims by health officials that the condition is “mild.”
A new peer-reviewed study shows more than two-thirds of adolescents with COVID-19 vaccine-related myopericarditis had persistent heart abnormalities months after their initial diagnosis, raising concerns for potential long-term effects.
The findings, published March 25 in the Journal of Pediatrics, challenge the position of U.S. health agencies, including the Centers for Disease Control and Prevention (CDC), which claim heart inflammation associated with the Pfizer and Moderna mRNA vaccines is “mild.”
Researchers at Seattle Children’s Hospital reviewed cases of patients younger than 18 years old who presented to the hospital with chest pain and an elevated serum troponin level between April 1, 2021, and Jan. 7, 2022, within one week of receiving a second dose of Pfizer’s vaccine.
While 35 patients fit the criteria, 19 were excluded for various reasons. Cardiac magnetic resonance imaging (MRI) of the remaining 16 patients was performed three to eight months after they were first examined. The MRIs showed 11 had persistent late gadolinium enhancement(LGE), although levels were lower than in previous months.
According to the study, “The presence of LGE is an indicator of cardiac injury and fibrosis and has been strongly associated with worse prognosis in patients with classical acute myocarditis.”
In a meta-analysis of eight studies, LGE was found to be a predictor of all-cause death, cardiovascular death, cardiac transplant, rehospitalization, recurrent acute myocarditis and requirement for mechanical circulatory support.
Similarly, an 11-study meta-analysis found the “presence and extent of LGE to be a significant predictor of adverse cardiac outcomes.”
Researchers said that while symptoms “were transient and most patients appeared to respond to treatment,” the analysis showed a “persistence of abnormal findings.”
The results “rais[e] concerns for potential longer-term effects,” researchers wrote, adding that they plan to repeat imaging at one year after the vaccine to assess whether abnormalities have resolved.
“The paper provides more evidence that myocarditis in adolescents that result from COVID-19 vaccines is very serious,” said Dr. Madhava Setty, senior science editor for The Defender.
“All patients had significantly elevated serum troponin levels indicative of heart damage. And LGE, which is indicative of poor outcome, was present in more than two-thirds of the kids.”
The study stated, “All patients had elevated serum troponin levels (median 9.15 ng/mL, range 0.65-18.5, normal < 0.05 ng/mL).”
“These young patients had a median troponin level of 9.15 — more than 20 times greater than the levels found in people suffering heart attacks,” Setty said.
Commenting on the study, Dr. Marty Makary, surgeon and public policy researcher at Johns Hopkins University, tweeted “CDC has a civic duty to rigorously study the long-term effects of vaccine-induced myocarditis.”
CDC has a civic duty to do rigorously study the long-term effects of vaccine-induced myocarditis. New follow-up study 3-8 months after myocarditis shows the MRI heart abnormality of late gadolinium enhancement seen in 63% of children. Merits further study. https://t.co/klPVsnqrkc
Dr. Anish Koka, a cardiologist, told The Epoch Times the study suggests 60% to 70% of teenagers who get myocarditis from a COVID vaccine may be left with a scar on their heart.
“Certainly, children who had chest pain severe enough to merit seeking medical attention need to at least make sure they get a follow-up MRI,” Koka said, adding that the findings “should have clear implications for the discussion around vaccines, especially for high-risk male teenagers … and definitely for vaccine mandates.”
Myocarditis, or inflammation of the heart, is a severe and life-shortening disease. It was virtually unknown in young people until it became a recognized side effect of mRNA COVID vaccines, especially in boys and young men.
Pericarditis is inflammation of the pericardium, a sac-like structure with two layers of tissue that surrounds the heart to hold it in place and help it work.
According to the CDC, the most at-risk group is 16- and 17-year-old males, who have reported rates of 69 per million after the second dose of Pfizer’s COVID vaccine, although that number is likely underreported.
The CDC presentation also reported that in three-month follow-up evaluations, less than one-third of adolescents 12 to 17 who suffered vaccine-induced myocarditis (reported in Vaccine Safety DataLink) had fully recovered.
The 69-per-million rate the CDC uses to determine the incidence of myocarditis in 16- and 17-year-olds came from the agency’s Vaccine Adverse Event Reporting System (VAERS) — a U.S. government-run database that receives reports of vaccine adverse events.
One of the biggest limitations of passive surveillance systems, like VAERS, is that the system “receives reports for only a small fraction of adverse events,” according to the Department of Health and Human Services website.
This incidence matches nearly exactly with findings from a study that used the Vaccine Safety DataLink system, which showed 37.7 12- to 17-year-olds per 100,000 suffered myo/pericarditis after their second vaccine dose.
This indicates an incidence rate that is almost six times higher than the 69-per-million rate reported by the CDC.
In a preprint study from Kaiser Permanente, the incidence of myocarditis in 18- to 24-year-old males post-vaccination was even higher — at 537 per million, or 7.7 times higher than the statistics reported by the CDC.
No such thing as ‘mild’ heart damage
A paper published Jan. 14 in Circulation summarized the clinical course of 139 young patients between the ages of 12 and 20 who were hospitalized for myocarditis following COVID vaccination.
Of those patients, 19% were taken into intensive care, two required infusions of potent intravenous drugs used to raise critically low blood pressure and every patient had an elevated troponin level.
Troponin is an enzyme specific to cardiac myocytes. Levels above 0.4 ng/ml are strongly suggestive of heart damage.
The paper concluded, “Most cases of suspected COVID-19 vaccine myocarditis occurring in persons <21 years have a mild clinical course with rapid resolution of symptoms.”
“We suppose [a ‘mild clinical course] refers to the 81% who did not go to the ICU or the fact that none died or required ECMO (Extracorporeal Membrane Oxygenation, a desperate means to keep the body oxygenated when a patient’s heart or lungs have completely failed),” wrote Setty and Josh Mitteldorf, Ph.D., a theoretical physicist, in an articlecritiquing the Circulation paper.
“When does a ‘mild clinical course’ require hospitalization for a two-day median length of stay?” they asked. “How does anyone know if symptoms rapidly resolve?”
“We don’t know what it will do to young boys in the long term, especially since every patient had some damage to their heart as evidenced by significantly abnormal troponin levels,” Setty and Mitteldorf wrote. “And we don’t fully understand the mechanism by which the vaccines cause myocarditis.”
She builds curves into her designs. So the cow always thinks it’s going back to where it started. To the field. To freedom. The cow plods on. “Just a bit further and I’ll be okay.” Until it is too late. The cow follows the last bend and arrives at the killing room. Within seconds, she’s immobilised in the crush, stunned and dispatched.
Think about the lockdowns. Social distancing. Masks. Vaccine passports. They’re building a slaughterhouse chute around us.
Most people won’t even notice. Once they’ve been tricked into having the jabs, they’re heavily invested in the narrative. They don’t want it to be untrue. So they’ll keep on complying. They’ll keep on having the boosters. Every six months. Then every three months. They’ll do whatever they are told.
”Just another week to flatten the curve.” “Just another freedom gone.” “Just another jab.”
The events of 9/11 tore the Bill of Rights to shreds. A dozen terrorist attacks could have brought in complete totalitarian control a decade ago. This isn’t about control. And it’s not about money. These people can print money. They can buy entire countries. So what is it about? In a word: resources.
A century ago, human population was 1.8 billion and a barrel of oil extracted 100 barrels of oil from the ground. Today human population is 8 billion and a barrel of oil yields just 5 barrels.
We’re rapidly approaching a zero sum game. The last ever barrel of oil. Remember the Deepwater Horizon disaster? They were drilling for oil 3.5 miles below sea level, in water almost a mile deep. The prize? Enough oil to meet global demand for 12 hours. That was 12 years ago. I believe that the elites have already made their decision. They are acting before it is too late.
Sixty four percent of the human population have already been jabbed. For a few tens of millions of carefully selected humans, there is a bright future indeed. The remaining resources will stretch for a thousand years. They will reach for the stars.
But if the elites don’t act, human population will continue to climb exponentially until modernity comes to an abrupt end in a few short decades. Along with all of the resources.
They’re ready to do away with the useless eaters. It’s 2022. Machines think, robots dance, and we just eat everything and burn stuff. Their stuff.
Ask yourself this question. Do the perpetrators really want control over the 8 billion consumers of their precious resources… or do they just want the resources? It’s a no-brainer. I believe that is why they’re pulling the plug now.
If they cull Western civilisation, they can halt 80% of global consumption in one hit. Then they can cull the Third World at their leisure.
So the vaccines do have a purpose, but it is not about profits or controlling who you can go to the movies with. That kind of control is expensive. It’s resource hungry. Our own governments are telling us that most of our jobs will be automated within a decade anyway.
They’re literally telling us that it’s over. We need to change the way people think about what’s been done to them.
The vaccine is NOT a means to bring in vaccine passports and totalitarian control. Stories about dark, dystopian futures for billions of people are just as much a fiction as tales of clean, renewable energy forever and an electric car for everyone.
The vaccine passports and totalitarian controls are simply tools to coerce us into taking the vaccine. How does the vaccine passport accomplish this? It starts with your livelihood. You lose your job. You become unemployable.
Then you can’t go to concerts or to the theatre. Or restaurants. Soon, you can’t go to supermarkets. Or convenience stores. Then you’re barred from doctor’s surgeries and dentists. And hospitals. Then you can’t get on a plane or train or ship. Or even a bus. Eventually, you can’t get car insurance or drive. Or leave your house. Or have a bank account. Or pay your bills. Or your taxes. Or own property. It’s a very slippery slope. Coupled with inflation and a cashless society, it will soon leave everyone dependent upon the State.
There are no exemptions to the vaccine. Even if you get spooked, or have a reaction to the jab, you’re still trapped inside the social credit system. Your COVID Pass will expire the moment you say, “No!”. You will be denied the basic freedoms of civilised society until you comply. You will stand at the brink of homelessness and hunger. And so you will keep on having the jabs. And getting sicker and sicker as your immune system deteriorates.
The slaughterhouse chute is almost complete. Our politicians are cheerfully helping to herd us into it with the stunning lack of vision that only politicians seem to possess.
If the government, judicial system, law enforcement, healthcare services, etc, are unsympathetic now, imagine how they’ll be when all the anti-vaxxers are sacked.
Meanwhile, the police will abuse their powers. The judges will throw our cases out. The consultants will shrug. The bankers will look at the bottom line. And the politicians will take their bribes as they have for centuries.
We need to black pill the man in the street and start a chain reaction of truth. He is probably less deeply hypnotised. We don’t have long. If we don’t create a stampede away from the slaughterhouse chute right now, we might as well give up and take the kill shot.
The ongoing Truckers for Freedom convoy in Ottawa has triggered a shockwave that is reaching all around the world. Even as our authoritarian federal regime continues to double down on measures and threatens to use brute force tactics against peaceful protesters, many provinces are nervously beginning to lay out a timeline for ending mandates.
But there is something important missing from the conversation surrounding the end of mandates. If the mandates are simply dropped today without calling out the underlying legal and ethical fallacy that was used to justify them, government overreach will have become normalized. We will be left without the legal protections to stop them from doing this to us again after the truckers go home. All it will take to put us back in a cage is for the government to point at the next wave, the next virus variant, or the next non-Covid emergency.
We will have normalized that our rights, our freedoms, our bodily autonomy, and even access to our lives are conditional privileges, subject to opinion polls and technocratic impulses and that they can be withdrawn again at any time, “for our safety.”
In March of 2020, in violation of the principles embedded in our constitutions, governments around the world convinced citizens to give their leaders and public institutions the authority to overrule individual rights in order to “flatten the curve.” That impulse went unchallenged under the false assumption that human rights violations could be justified as long as the benefits to the majority outweighed the costs to the minority. By accepting this excuse for overriding unconditional rights, we transformed ourselves into an authoritarian police state where “might makes right.” That is the moment when all the checks and balances in our scientific and democratic institutions stopped functioning.
Liberal democracy was built around the principle that individual rights must be unconditional. In other words, they are meant to supersede the authority of government. Consequently, individual rights (such as bodily autonomy) were meant to serve as checks and balances on government power. They were meant to provide a hard limit to what our government can do to us without our consent.
If the government cannot override your rights to bend you to its will, then it will be forced to try to convince you by talking with you. That forces government to be transparent and to engage in meaningful debate with critics. Your ability to say NO, and to have your choice respected, is the difference between a functioning liberal democracy and an authoritarian regime.
The natural instinct of fearful people is to control those around them. Unconditional rights force people to negotiate voluntary participation in collective solutions. Thus, unconditional rights prevent the formation of echo chambers and provide an important counter-weight to rein in uncontrolled panic. When no-one has the option to use the brute force of State power to force others to submit to what they think is “the right thing to do,” then the only path forward is to keep talking to everyone, including to “fringe minorities” with “unacceptable views.” When we allow rights to become conditional, it is virtually a certainty that during a crisis, panicked citizens and opportunistic politicians will give in to their worst impulses and trample those who disagree with them.
Unconditional individual rights prevent governments from taking unwilling citizens on crusades. They prevent scientific institutions from transforming themselves into unchallengeable “Ministries of Truth” that can double down on their mistakes to avoid accountability. They ensure that the checks and balances that make science and democracy work do not break down in the chaos of a crisis. In the heat of an emergency when policy decisions are often made on the fly, unconditional rights are often the only safeguards to protect minorities from panicked mobs and self-anointed kings.
If we allow our leaders to normalize the idea that rights can be switched off during emergencies or when political leaders decide that “the science is settled,” then we are giving the government terrifying and unlimited power over us. It gives those who control the levers of power the authority to turn off access to your life. That turns the competition for power into a zero-sum game: the winners become masters, the losers become serfs. It means you can no longer afford to allow the other side to win an election, at any cost, nor agree to a peaceful transfer of power, because if you lose the winning team becomes the master of your destiny. And so, a zero-sum game of brutal power politics is set in motion. Unconditional individual rights are the antidote to civil war. Liberal democracy collapses without them.
Withdrawing mandates because “the Omicron variant is mild” or because “the costs of continuing the measures outweigh the benefits” does not undo what has been normalized and legitimized. If the legitimacy of mandates is not overturned, you will not be going back to your normal life. It may superficially look similar to your life before Covid, but in reality you will be living in a Brave New World where governments temporarily grant privileges to those who conform with the government’s vision of how we should live. You will no longer be celebrating your differences, cultivating your individuality, or making your own free choices. Only conformity will enable you to exist. You will be living under a regime in which any new “crisis” can serve as justification to impose restrictions on those who don’t “get with the program” as long as mobs and technocrats think the restrictions are “reasonable.” You will no longer be the master of your own life. A golden cage is still a cage if someone else controls the lock on the door.
Politicians and public health authorities MUST be forced to acknowledge that mandates are a violation of civil liberties. The public MUST be confronted by the fact that liberal democracy ceases to exist without the unconditional (inalienable) safeguards of individual rights and freedoms. The public MUST recognize that science ceases to function when mandates can be used to cut off scientific debates. Our governments and our fellow citizens MUST be made to understand that unconditional rights are especially important during a crisis.
If the legal and ethical fallacies that were used to justify mandates are not called out as inexcusable violations of our constitutional rights, we will have inadvertently normalized the illiberal idea that, as long as someone in a lab coat says it’s okay, this can be done to us again, at any time, whether to fight the next wave of Covid, to take away freedoms to fight “climate change”, to seize assets to solve a government debt crisis, or simply to socially engineer outcomes according to whatever our leaders define as a “fairer and more equitable world”.
How we navigate the end of mandates determines whether we win our freedom or whether we allow our leaders to normalize a Brave New World with conditional rights that can be turned off again during the next “emergency.”