The fact is that women who receive the Pfizer mRNA vaccine may be putting their unborn babies at a very high risk of dying during the pregnancy. So why do Pfizer and the FDA continue to recommend that pregnant women receive the Pfizer mRNA vaccine?
To understand the increased risks, we need to understand first what is normal; that is, how often does a baby die during an unvaccinated woman’s pregnancy? Early in a pregnancy, miscarriage or spontaneous abortion (the death of a baby before 13 weeks gestation) happens in 1 of 10 (10%) pregnancies (https://www.acog.org/womens-health/faqs/early-pregnancy-loss). Later in a pregnancy, the risk of a baby dying decreases dramatically: stillbirths (the death of a baby after 20 weeks gestation) occur in 1 in 160 (0.6%) pregnancies (https://www.marchofdimes.org/complications/stillbirth.aspx).
These are the normal background rates of in utero death. Yet after mothers receive the Pfizer mRNA vaccine, in utero deaths appear to be much, much higher. The truth lies in Pfizer’s own documents submitted to the US Food and Drug Agency.
Pfizer reported that pregnancy outcomes were available for only 32 of 270 pregnancies and 4 associated fetus/baby cases (p. 12, https://www.phmpt.org/wp-content/uploads/2022/04/reissue_5.3.6-postmarketing-experience.pdf). In these 36 cases, 28 babies (78%) died after their mothers received the Pfizer mRNA vaccine. Pfizer and the FDA knew by April 2021 that the babies’ mortality rate may have been much greater than normal. This is a serious claim, so it’s important to explain where this number comes from.
Pfizer’s Table 6 (excerpted in Fig. 1, below) notes that 124 of 270 vaccinated mothers (46%) experienced adverse or serious adverse events. A total of 75 of these mothers (28%) and 4 additional unborn babies or neonates were reported to have had serious adverse events after the mothers received the mRNA vaccine. Of the 36 babies for which Pfizer knew the outcome, 25 died before birth and 3 died at birth. The babies’ deaths are categorized as follows:
23 spontaneous abortions
2 spontaneous abortions with intrauterine death
2 premature births with neonatal death
1 spontaneous abortion with neonatal death
Thus 28 out of 36 babies with known outcomes died at or before birth—a crude mortality rate of 78%.This suggests a mortality rate much higher than normal (10% for early pregnancies; less than 1% for pregnancies that last longer than 20 weeks). But we must keep in mind that these data are incomplete; Pfizer reported no information on 238 babies. For a truly valid estimate of the mortality rate, one would need either the complete data set or a random sample. Pfizer collected neither.
Just the suggestion that more babies were dying during pregnancy should have raised alarms at Pfizer. Instead Pfizer concluded that the benefits of the mRNA vaccine were worth the risks of a pregnant woman losing her baby.
So the question remains: Why do Pfizer and the FDA continue to allow pregnant women to be vaccinated? They know that unborn babies may be at increased risk of death from the Pfizer mRNA vaccine. Why aren’t pregnant women warned of these risks?
Our enemies are obsessed with jamming our OODA Loops. They do not want us to have even a moment to think. An OODA loop is a decision making process: observe–orient–decide–act. We take in information, and we make a decision on how to act to change things. Our enemies keep distracting us with constantly changing information, and we keep getting stuck in the OO stage, never making decisions, never acting to change things, because we are constantly trying to figure out the nature of the trap we are caught in. But that is the trap we are caught in! We end up stuck in endless puzzling debates, making no productive plans to achieve victory in even one small way.
When a fresh news story gets hyped up, and people say “oh oh they are just distracting us”, it is THINKING TIME they are distracting us from. A moment for the dust to settle, for even a minute of propaganda-free time, to be able to make a plan to counter our enemy’s plans. They cannot allow us this minute. We are allowed no firm place to stand. They have to bombard us with useless factoids and storylines 24/7, little rabbit holes and dead-ends and intrigue and drama, or else we might form together into something capable of defeating their psychological operations. Distraction and overload is their primary weapon against us. Unfortunately, we keep falling for this trick.
The OODA loop is the cycle observe–orient–decide–act, developed by military strategist and United States Air Force Colonel John Boyd. Boyd applied the concept to the combat operations process, often at the operational level during military campaigns. It is now also often applied to understand commercial operations and learning processes. The approach explains how agility can overcome raw power in dealing with human opponents. It is especially applicable to cyber security and cyberwarfare.
The OODA loop has become an important concept in litigation, business,law enforcement, and military strategy. According to Boyd, decision-making occurs in a recurring cycle of observe–orient–decide–act. An entity (whether an individual or an organization) that can process this cycle quickly, observing and reacting to unfolding events more rapidly than an opponent, can thereby “get inside” the opponent’s decision cycle and gain the advantage.
Monkeypox can only be a serious problem for humans if it has been meddled with. For instance, GOF, ( gain of function )
The National Institute of Allergy and Infectious Diseases, directed by Dr. Anthony Fauci, last year paid $9.8 million to government researchers to test a monkeypox treatment. Some called the timing “curious” given the recent outbreak of the virus.
The National Institute of Allergy and Infectious Diseases (NIAID), directed by Dr. Anthony Fauci, last year paid $9.8 million to government researchers to test a monkeypox treatment, the National Pulse reported.
According to the National Institutes for Health (NIH), which oversees the NIAID, the research began Sept. 28, 2020 and will conclude Sept. 27, 2025. Its goal is to carry out a “randomized, placebo-controlled trial of the safety and efficacy of tecovirimat for the treatment of patients with monkeypox virus disease.” It is unclear if the grant provided for any payments in 2020.
The NIAID awarded the grant to the Frederick National Laboratory for Cancer Research, a federally funded research and development center in Frederick, Maryland, supported by the National Cancer Institute.
According to the grant abstract:
“The similarity between monkeypox and the variola [smallpox] virus, coupled with concerns about the potential of the variola virus as a potential bioterrorism agent, have placed monkeypox treatments at the forefront of public health and scientific research agendas in many countries.”
On May 25, SIGA Technologies Inc.announced that it received approval from the U.S. Food and Drug Administration (FDA) for an intravenous formulation of the antiviral tecovirimat (called TPOXX) for the treatment of smallpox.
Although smallpox was eradicated in 1980, the treatment was developed in the event smallpox were to be used as a bioweapon.
The U.S., Canada and Europe have approved an oral formulation of TPOXX for treating smallpox, and Europe also approved it for treating monkeypox and cowpox.
As of May 30, the NIH project had not generated any publicly available studies, papers or patents, according to The National Pulse.
The National Pulse called the timing of the grant “curious,” as it comes while pharmaceutical giants including Pfizer and Johson & Johnson are making record-level profits due to the COVID-19 pandemic.
Dr. Lori Dodd, a mathematical statistician in the biostatistics research branch of NIAID, is the project’s principal investigator.
On a recent segment of The Hill’s “Rising,” co-hosts Briahna Joy Gray and Kim Iversen reminded viewers that Dodd was “exposed for her involvement in the agency’s reported data altering of remdesivir trials to make [remdesivir] seem more effective against COVID.”
Iversen and Gray also found the timing of the funding suspicious.
“It could just be coincidental,” said Iversen, “ … but I will say that there is something very suspect about the fact that they started working on identifying treatments for monkeypox in September of 2020. This has been a virus that’s been around since 1970.”
However, Gray said, “in a world where everyone’s certainly concerned about viruses because of COVID-19, maybe the money simply started to flow in the fall of 2020.”
“What’s odd,” responded Iversen, “is that there’s now suddenly an outbreak [of monekypox] and that outbreak is making headlines and it’s spreading all around the world.”
Iversen implied the NIH may be hoping to develop a new treatment for monkeypox as public fear of the disease grows.
As The Defender has reported, others also questioned how unexpected the monkeypox outbreak was after learning about a March 2021 tabletop simulationof a hypothetical deadly outbreak of monkeypox predicted to occur in May 2022.
. It’s the biggest European country, bigger than France. Donbass territories, occupied by Russia, are as big as Switzerland. What is happening now is not a small local conflict, but a hazard for the whole world.» Orig. by Olena Karpenko
For those who ask: “Why does Ukraine matter?”
1st in Europe in proven recoverable reserves of uranium ores; 2nd place in Europe and 10th place in the world in terms of titanium ore reserves; 2nd place in the world in terms of explored reserves of manganese ores (2.3 billion tons, or 12% of the world’s reserves); 2nd largest iron ore reserves in the world (30 billion tons); 2nd place in Europe in terms of mercury ore reserves; 3rd place in Europe (13th place in the world) in shale gas reserves (22 trillion cubic meters) 4th in the world by the total value of natural resources; 7th place in the world in coal reserves (33.9 billion tons)
Ukraine is an agricultural country: 1st in Europe in terms of arable land area; 3rd place in the world by the area of black soil (25% of world’s volume); 1st place in the world in exports of sunflower and sunflower oil; 2nd place in the world in barley production and 4th place in barley exports; 3rd largest producer and 4th largest exporter of corn in the world; 4th largest producer of potatoes in the world; 5th largest rye producer in the world; 5th place in the world in bee production (75,000 tons); 8th place in the world in wheat exports; 9th place in the world in the production of chicken eggs; 16th place in the world in cheese exports. Ukraine can meet the food needs of 600 million people.
Ukraine is an industrialized country: 1st in Europe in ammonia production; 2-е Europe’s and 4th largest natural gas pipeline system in the world (142.5 bln cubic meters of gas throughput capacity in the EU); 3rd largest in Europe and 8th largest in the world in terms of installed capacity of nuclear power plants; 3rd place in Europe and 11th in the world in terms of rail network length (21,700 km); 3rd place in the world (after the U.S. and France) in production of locators and locating equipment; 3rd largest iron exporter in the world 4th largest exporter of turbines for nuclear power plants in the world; 4th world’s largest manufacturer of rocket launchers; 4th place in the world in clay exports 4th place in the world in titanium exports 8th place in the world in exports of ores and concentrates; 9th place in the world in exports of defence industry products; 10th largest steel producer in the world (32.4 million tons).
Source: Andriy Futey Ukrainian Congress Committee of America Ukrainian World Congress – Свiтовий Конґрес Українців
As many as six million British households could be subjected to power cuts this winter if Russian gas supplies to Europe stop, The Times reported Sunday, citing a Whitehall document.
It said that imports of natural gas from Norway could halve next winter amid surging EU demand. Britain buys around half of its total supplies from the Nordic country.
Shipments of liquified natural gas from major producers such as the United States and Qatar could also halve this winter, the UK government warned, pointing to fierce global competition for supplies of the fuel.
Meanwhile, interconnectors from the Netherlands and Belgium could also be cut off in winter, as the two countries struggle meeting their own demand.
The UK, which has vowed to end the importation of Russian oil by the end of the year, is now seeking to bolster electricity supply by extending the life of its coal and aging nuclear power stations
An Inquest, Likely due to the family not expecting an ‘unexplained’ death and pushing for answers, is further proof of the dangers of the Pfizer Vaccine. Another healthy young woman, daughter, mother and wife has lost her life from being coerced by our lying governments, global ‘health agencies’ and big Pharma.
She leaves behind her year old son… How many more will we lose, how many children?
‘A post-mortem examination on the body of Dawn Wooldridge had previously proved inconclusive but an inquest heard on Thursday that the unexpected death, which happened 11 days after Dawn’s first Covid jab, was likely caused as a result of the vaccination.
The 36-year-old was found dead in her home by her brother in June last year, after she failed to collect her five-year-old son from school that day.
In a statement to the Berkshire coroner by Dawn’s husband, Ashley, he said: “We met on holiday in Turkey and we have been married for seven years this year.’
Davos Man, his World Economic Forum, and his Servants
The purpose of this essay and the accompanying spreadsheet is to provide you with information and transparency about who these people are, where they come from, what their ethics and policy positions are, where they work, what sectors they work in, and when they were trained to do the bidding of the World Economic Forum (“WEF”).
These people have been trained to believe in and support a globalist form of unelected government, in which business is at the centre of the management and decision-making process. They are fundamentally anti-democratic, and their views are both fundamentally corporatist and globalist, which is another way of saying that they are for totalitarian fascism – the fusion of the interests of business with the power of the state – on a global scale.
The Malone Institute, in collaboration with the Pharos Foundation and Pharos Media Productions in Sweden, has invested months of time and hundreds of labour hours to mine existing and historic publicly available data sources to develop a detailed summary of graduates from two WEF training programs; Global Leaders of Tomorrow (a one-year program that ran from 1993 to 2003) and Young Global Leaders (a five-year program started 2004/2005 and still running).
The current 100 WEF full members (“Strategic Partners”) are drawn from the largest corporations in the world, together with their owners and managers (referred to as “Davos Man”). The list of corporations, owners and managers who control the WEF is not disclosed and membership can only be inferred indirectly. However, the WEF members do not act alone, but have developed various groups of globally distributed trainees who generally act in accordance with the detailed policies and positions developed and distributed by WEF leadership. These training programs have been operating for over three decades, resulting in placement, distribution and rapid advancement of many thousands of WEF-trained operatives throughout the world. WEF chairman Klaus Schwab has famously claimed that these operatives have been strategically inserted into key positions in various governments, as well as influential spots in key industries such as media, finance, and technology.
“Davos Man” is a term coined by former Harvard University Director of the Centre for International Affairs Professor Dr. Samuel Huntington (1927-2008) to define an emerging group of economic elites who are members of a social caste which has “little need for national loyalty, view national boundaries as obstacles that are thankfully vanishing, and see national governments as residues from the past whose only useful function is to facilitate the elite’s global operations.” The title of his prescient 2004 article published in The National Interest is telling: “Dead Souls: The Denationalisation of the American Elite”.
In a 2005 article published in The Guardian titled “Davos man’s death wish”, Timothy Garton Ash described Davos Man and the World Economic Forum:
“Davos Man is mainly white, middle-aged and European or Anglo-Saxon. Of course, some of the participants at this year’s five-day meeting of the World Economic Forum in the Swiss mountain resort were Indian, Chinese, African or/and women. But they continue to be a minority. The dominant culture of Davos remains that of white western man
“Davos man has a troublesome pre-history of combining brilliance and stupidity, of being blinded by national and ideological prejudice to his own long-term interest and destroying with one hand what he has built with the other.”
Wikipedia defines “megalomania” as “an obsession with power and wealth, and a passion for grand schemes.” It also relates this term to the following psychological terms: Narcissistic personality disorder, Grandiose delusions, and Omnipotence (psychoanalysis), a stage of child development. Davos Man fits the definition of megalomania and has acquired what he believes are the financial and political resources to try to force his obsession and grand schemes on the world, and to force you, your family, and the world to comply with his vision.
Regarding the WEF, Andrew Marshall developed a brief introductory summary which I strongly recommend reading, published in a 2015 article entitled “World Economic Forum: a history and analysis”. The membership of the WEF is divided into three categories: Regional Partners, Industry Partner Groups, and the most esteemed, the Strategic Partners. Membership fees from corporations and industry groups finance the Forum and provide the member company with extra access and to set the agenda. A full list of current Strategic Partners can be found HERE.
“Why should you care?”
The WEF is the organisation which has masterminded the globally harmonised planning, development and implementation of the lockdowns, mandates, authoritarian vaccine campaigns, suppression of early treatment options, global targeting of dissenting physicians, censorship, propaganda, information and thought control programs which we have all experienced since late 2019. This is the organisational structure used by the ones who have sought to control and manage the world to advance the economic and political interests of their members through the ongoing “Great Reset” (as named and described by their chairman Klaus Schwab) by exploiting and exacerbating the social and economic disruption which they have artificially and intentionally crafted since SARS-CoV-19 began spreading across the world.
The musings and plans of this trade organisation read and sound like the implausible sinister plot of an international spy novel concocted by a second-rate version of Ian Fleming, John Le Carre, or Robert Ludlum. Unfortunately, they are backed by the financial resources of many of the wealthiest people in the world. For examples of the muddled thinking and pseudo-science which these self-appointed masters of the universe proudly publish, I recommend that you do your best to read COVID-19: The Great Reset, The Great Narrative for a better future (both by Klaus Schwab and Thierry Malleret), and How to Prevent the Next Pandemic (by Bill Gates). A detailed interactive summary of their policy positions and the interrelationships of those policies (“transformation map”) can be found HERE and for COVID-19, HERE.
“What can you do about it?”
After all you have seen and experienced since September 2019, please look in the mirror and ask yourself these two questions:
“Are these people I can trust with my future and that of my children?”
“Do they represent my interests, values, and what I believe in?”
If you decide that you cannot trust them, or that they do not share your interests and values, then it is high time to act to prevent them from taking control of all aspects of your life. Otherwise, the WEF seeks to take away everything you own, and to completely control all aspects of your life. One of the key predictions of their “Global Future Councils” is that by 2030, you (or your children) will own nothing, and will be happy. Here is a LINK to other aspects of their vision of tomorrow.
Whatever your answer, you deserve to know who these people are that wish to control the world, your daily life, what information you can access, what you are allowed to think, and what you are allowed to own. You deserve to know who they represent, and what are their names. The purpose of this essay and the accompanying spreadsheet is to provide you with information and transparency about who these people are, where they come from, what their ethics and policy positions are, where they work, what sectors they work in, and when they were trained to do the bidding of the WEF (there are often close bonds between members of the same class year).
These people have been trained to believe in and support a globalist form of unelected government, in which business is at the centre of the management and decision-making process. They have been trained to advance the interests of a global transnational government which represents a public-private partnership in which the business interests of the WEF members take precedence over the constitution of the United States. The WEF believes that the concept of independent nation-states is obsolete and must be replaced with a global government which controls all. They are fundamentally anti-democratic, and their views are both fundamentally corporatist and globalist, which is another way of saying that they are for totalitarian fascism – the fusion of the interests of business with the power of the state – on a global scale. These people do not represent the interests of the nation-state in which they reside, work, and may hold political office, but rather their allegiance appears to be to the WEF vision of a dominant world government which has dominion over nations and their constitutions. In my opinion, in the case of those trainees and WEF members who are in politics, and particularly those who have been used to “penetrate the global cabinets of countries”, these persons should be forced to register as foreign agents within their host countries.
Davos Man’s Servants are Foreign Agents. The full title of the US Foreign Principal Registration Act of 1938 (FARA) is “An Act to require the registration of certain persons employed by agencies to disseminate propaganda in the United States and for other purposes.” Citing Wikipedia,
“The Foreign Agents Registration Act (FARA) (2 U.S.C. § 611 et seq.) is a United States law requiring persons engaged in domestic political or advocacy work on behalf of foreign interests to register with the Department of Justice and disclose their relationship, activities, and related financial compensation. Its purpose is to allow the government and general public to be informed of the identities of individuals representing the interests of foreign governments or entities. The law is administered and enforced (or not…) by the FARA Unit of the Counterintelligence and Export Control Section (CES) in the National Security Division (NSD).”
The List of WEF Trainees
The Malone Institute (primarily Dr. Jill Glasspool-Malone and Anita Hasbury-Snogles), in collaboration with the Pharos Foundation and Pharos Media Productions in Sweden, has invested months of time and hundreds of labour hours to mine existing and historic publicly available data sources to develop a detailed summary of graduates from two WEF training programs; the World Economic Forum’s Global Leaders of Tomorrow (a one-year program that ran from 1993 to 2003) and Young Global Leaders (a five-year program started 2004/2005 and still running). Pharos foundations’ summary can be found here. These people have been intentionally and internationally deployed as foreign agents representing the interests of the WEF members to “penetrate the global cabinets of countries” as well as a wide range of key business sectors including banking/finance, other business sectors (including health and biotechnology), academia and health, media, technology, logistics, arts and culture, sports, politics and government, think tanks, telecommunications, real estate, financial investment/holding companies, a variety of non-governmental organisations, energy, aerospace and military, food and agriculture.
This list can be found and downloaded at the following link:
The list contains a summary of the graduates of the World Economic Forum’s Global Leaders of Tomorrow (a one-year program that ran from 1993 to 2003) as well as the Young Global Leaders (a five-year program started 2004/2005 and still running).
To create this list, the Malone Institute and the Pharos Foundation have used World Economic Forum search engines and cross-checked published lists, Wayback Machine archives, Wikispooks, and other complementary sources. It may not be 100% accurate, but we have done our best to make it as correct and updated as possible. Some people have been removed from the WEF website, and some were never listed but have been identified by Klaus Schwab himself as members of his young global agents of change. We have done extensive manual research in order to identify and verify those for whom very little information has been provided. When missing, there has been an attempt to find and add relevant countries, positions etc. When identified, links have been provided to existing biographies, primarily those included in World Economic Forum webpages, or else Wikipedia, LinkedIn, company pages, or articles. In some cases (when available) we have also provided links to organisations they have worked at. When possible, positions and organisations in many cases have been updated to the most recent identifiable.
The Sector designations chosen by WEF have changed over the years, so the spreadsheet uses the most descriptive term for their updated sector and position, but in some cases we have added our own – especially in the Business sector where we have added Sub-sectors for more detailed information. The Region designations used by WEF have also changed over the years, so we have used simpler geographical regions. We have added extra columns in the spreadsheet for Sex, Political position, Health connection, and finally Notes for additional or relevant information.
This list is open to corrections and additions, should anyone spot an error or have more information. Please write to us at info@MaloneInstitute.org if you have additional information, details, or corrections.
So that you can cross-check for yourself, below are provided hyperlinked sources for this summary, which includes only the listed groups (GLT = Global Leaders of Tomorrow, YGL = Young Global Leaders). There are additional WEF trainee groups including “Young Scientists”, and these will be the focus of future similar summary spreadsheets. The lists below do not contain the full documentation of the members found on our master list above.
According to economist Richard Werner, who was selected for the GLT program in 2003, the Global Leaders of Tomorrow program (GLT) was closed down and rebooted as a more controllable group called the “Young Global Leaders” (YGL) because too many people were asking difficult questions in the forum (see “Last American Vagabond” podcast titled “COVID Measures And The Central Controls Over The Economy” here). Many of the more recently graduate classes are explicitly identified as revolutionaries who are “Driving the Fourth Industrial Revolution” on behalf of the WEF.
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]