First Look Look with First Western Journalist In Russia & DPR Controlled Azovstal Territory Mariupol (Special Report)
After many months of intense fighting in Mariupol fighting has come to almost a standstill as of the newest ceasefire declared yesterday. 05/06/22. A month ago we should you how there was intense street battles across the city but day by day as DPR and Russian forces have taken control of more and more parts of the city the fighting has winded down to just a very small pocket of the city with only some Ukraine forces being in part of the Azovstal plant underground with many civilians. Yesterday I spent the day on the Azovstal territory a only heard one explosion. At least 12 civilians were released by the Azov. In this report I show you part of the territory of the Azovstol and talked to the Russian and DPR soldiers who are fighting for the Azovstal.
There are talks among the locals that the Russian and DPR forces are planning a May 9th Victory day celebration in Mariupol. Kids play freely in the streets in most of the city. Weeks ago Russia declared victory in Mariupol. The city is being cleaned and already some areas starting to be rebuilt. Life is coming back to Mariupol. It seems it is just a matter of time before the Azovtstal plant and Mariupol no longer has any Ukrainian troops in it so there is no question that the major fighting is over. Now it is time for our team to move forward to some of the other breaking news areas in Donbass and beyond
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).
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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.
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.”
While the US is planning to increase its military presence in Eastern Europe to “protect its allies against Russia”, internal documents show what American “protection” in practical terms means.
The Pentagon has conducted biological experiments with a potentially lethal outcome on 4,400 soldiers in Ukraine and 1,000 soldiers in Georgia. According to leaked documents, all volunteer deaths should be reported within 24 h (in Ukraine) and 48 h (in Georgia).
Both countries are considered the most loyal US partners in the region with a number of Pentagon programs being implemented in their territory. One of them is the $2.5 billion Defense Threat Reduction Agency (DTRA) Biological engagement program which includes research on bio agents, deadly viruses and antibiotic-resistant bacteria being studied on the local population.
Project GG-21: “All volunteer deaths will be promptly reported”
The Pentagon has launched a 5-year long project with a possible extension of up to 3 years code-named GG-21: “Arthropod-borne and zoonotic infections among military personnel in Georgia”. According to the project’s description, blood samples will be obtained from 1,000 military recruits at the time of their military registration physical exam at the Georgian military hospital located in Gori.
The samples will be tested for antibodies against fourteen pathogens:
The amount of blood draw will be 10 ml. Samples will be stored indefinitely at the NCDC (Lugar Center) or USAMRU-G and aliquots might be sent to WRAIR headquarters in US for future research studies. Walter Reed Army Institute of Research (WRAIR) is the largest biomedical research facility administered by the U.S. Department of Defense. The results of the blood testing will not be provided to the study participants.
Such a procedure cannot cause death. However, according to the project report, “all volunteer deaths will be promptly reported (usually within 48 h of the PI being notified)” to the Georgian Military Hospital and WRAIR.
The soldiers’ blood samples will be stored and further tested at the Lugar Center, a $180 million Pentagon-funded facility in Georgia’s capital Tbilisi.
The Georgian project GG-21 has been funded by DTRA and implemented by American military scientists from a special US Army unit code-named USAMRU-G who operate in the Lugar Center. They have been given diplomatic immunity in Georgia to research bacteria, viruses and toxins without being diplomats. This unit is subordinate to the Walter Reed Army Institute of Research (WRAIR).
Documents obtained from the US Federal contracts registry show that USAMRU-G is expanding its activities to other US allies in the region and is “establishing expeditionary capabilities” in Georgia, Ukraine, Bulgaria, Romania, Poland, Latvia and any future locations. The next USAMRU-G project involving biological tests on soldiers is due to start in March of this year at the Bulgarian Military Hospital in Sofia.
Project UP-8: All deaths of study participants should be reported within 24 h
The Defense Threat Reduction Agency (DTRA) has funded a similar project involving soldiers in Ukraine code-named UP-8: The spread of Crimean-Congo hemorrhagic fever (CCHF) virus and hantaviruses in Ukraine and the potential need for differential diagnosis in patients with suspected leptospirosis. The project started in 2017 and was extended few times until 2020, internal documents show.
According to the project’s description, blood samples will be collected from 4,400 healthy soldiers in Lviv, Kharkov, Odesa and Kyiv. 4,000 of these samples will be tested for antibodies against hantaviruses, and 400 of them – for the presence of antibodies against Crimean-Congo hemorrhagic fever (CCHF) virus. The results of the blood testing will not be provided to the study participants.
There is no information as to what other procedures will be performed except that “serious incidents, including deaths should be reported within 24 hours. All deaths of study subjects that are suspected or known to be related to the research procedures should be brought to the attention of the bioethics committees in the USA and Ukraine.”
DTRA has allocated $80 million for biological research in Ukraine as of 30 July 2020, according to information obtained from the US Federal contracts registry. Tasked with the program is the US company Black &Veatch Special Projects Corp.
Another DTRA contractor operating in Ukraine is CH2M Hill. The American company has been awarded a $22.8 million contract (2020-2023) for the reconstruction and equipment of two biolaboratories: the State Scientific Research Institute of Laboratory Diagnostics and Veterinary-Sanitary Expertise (Kyiv ILD) and the State Service of Ukraine for Food Safety and Consumer Protection Regional Diagnostic Laboratory (Odesa RDL).
US personnel are indemnified for deaths and injuries to the local population
The DTRA activities in Georgia and Ukraine fall under the protection of special bilateral agreements. According to these agreements, Georgia and Ukraine shall hold harmless, bring no legal proceedings and indemnify the United States and its personnel, contractors and contractors’ personnel, for damage to property, or death or injury to any persons in Georgia and Ukraine, arising out of activities under this Agreement. If DTRA-sponsored scientists cause deaths or injuries to the local population they cannot be held to account.
Furthermore, according to the US-Ukraine Agreement, claims by third parties for deaths and injuries in Ukraine, arising out of the acts or omissions of any employees of the United States related to work under this Agreement, shall be the responsibility of Ukraine.
Russia has uncovered the US linked bioweapon facilities in Ukraine. I reported when this started that Putin was not doing the atrocities that the media say he has.
His main goal was to take down the Biolabs he knew the US had in Ukraine because they were a threat to his national security.
The link below is a Russian spokeswoman demanding an explanation from the US as to why they have weapons of mass destruction ( WMD ) which is extremely hypocritical after invading Iraq and accusing Saddam Hussein when the US has had them all along. One chemical weapon found was “Anthrax”