“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.”

“IVM can inhibit the replication of flavivirus by targeting the NS3 helicase [17]; 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 [18]. 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 [19]. In addition, IVM shows potential for clinical application in asthma [20] and neurological diseases [21]. Recently scientists have discovered that IVM has a strong anticancer effect.”

“After treatment with IVM, the proliferation of multiple breast cancer cell lines including MCF-7, MDA-MB-231 and MCF-10 was significantly reduced.”

“IVM regulates the tumor microenvironment and mediates immunogenic cell death, which may be a new direction for research exploring anticancer mechanisms in the future.”

“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)[39].”

“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 [41].”

“IVM could inhibit the development of hepatocellular carcinoma by blocking YAP1 activity in spontaneous liver cancer Mob1b-/- mice [43].”

“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 [48].”

“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 [50]. Interestingly, IVM also restored the sensitivity of the triple-negative breast cancer to the anti-estrogen drug tamoxifen [36], 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 [51].”

“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 [51].”

“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 [56]. 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.”

“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 [58]. 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 [59].”

“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 [69]. 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 [70]. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43]. 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 [50]. In addition, IVM could reduce the metastasis of lung cancer cells by inhibiting EMT.”

“Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity [73]. 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 [74]. However, NAC reversed the effect of IVM, which indicated that IVM increased TFE3-dependent autophagy through the ROS signaling pathway.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835698/

“So far, at least 235 clinically-approved, non-cancer drugs have proven antitumor activity either in vitro, in vivo, or even clinically. Among these, ivermectin, an antiparasitic compound of wide use in veterinary and human medicine, is clearly a strong candidate for repositioning, based on the fact that i) it is very safe, causing almost no side-effects other than those caused by the immune and inflammatory responses against the parasite in infected patients, and ii) it has proven antitumor activity in preclinical studies. On the other hand, it is now evident that the use of very selective “unitargeted” drugs is commonly associated to early development of resistance by cancer cells, hence the use of “dirty” or “multitargeted” drugs is important to explore. In this sense, ivermectin has this potential as it modulates several targets such as the multidrug resistance protein (MDR), the Akt/mTOR and WNT-TCF pathways, the purinergic receptors, the PAK-1 protein, certain cancer-related epigenetic deregulators such as SIN3A and SIN3B, RNA helicase activity, while stimulates chloride channel receptors leading to cell hyperpolarization, and down-regulates stemness genes to preferentially target cancer stem-cell like population, at least in breast cancer. Importantly, the in vitro and in vivo antitumor activities of ivermectin are achieved at concentrations that can be clinically reachable based on the human pharmacokinetic studies done in healthy and parasited patients. Thus, existing information on ivermectin could allow its rapid move into clinical trials for cancer patients.”

https://www.sciencedirect.com/science/article/pii/S1043661820315152

“• Ivermectin effectively suppresses the proliferation and metastasis of cancer cells and promotes cancer cell death at doses that are nontoxic to normal cells.

• Ivermectin shows excellent efficacy against conventional chemotherapy drug-resistant cancer cells and reverses multidrug resistance.

• Ivermectin combined with other chemotherapy drugs or targeted drugs has powerful effects on cancer.

• The structure of crosstalk centered on PAK1 kinase reveals the mechanism by which ivermectin regulates multiple signaling pathways.

• Ivermectin has been used to treat parasitic diseases in humans for many years and can quickly enter clinical trials for the treatment of tumors.”

https://pubmed.ncbi.nlm.nih.gov/32474842/

Purpose:

Ivermectin is an antiparasitic drug that exhibits antitumor effects in preclinical studies, and as such is currently being repositioned for cancer treatment. However, divergences exist regarding its employed doses in preclinical works. Therefore, the aim of this study was to determine whether the antitumor effects of ivermectin are observable at clinically feasible drug concentrations.

Methods:

Twenty-eight malignant cell lines were treated with 5 μM ivermectin. Cell viability, clonogenicity, cell cycle, cell death and pharmacological interaction with common cytotoxic drugs were assessed, as well as the consequences of its use on stem cell-enriched populations. The antitumor in vivo effects of ivermectin were also evaluated.

Results:

The breast MDA-MB-231, MDA-MB-468, and MCF-7, and the ovarian SKOV-3, were the most sensitive cancer cell lines to ivermectin. Conversely, the prostate cancer cell line DU145 was the most resistant to its use. In the most sensitive cells, ivermectin induced cell cycle arrest at G0-G1 phase, with modulation of proteins associated with cell cycle control. Furthermore, ivermectin was synergistic with docetaxel, cyclophosphamide and tamoxifen. Ivermectin reduced both cell viability and colony formation capacity in the stem cell-enriched population as compared with the parental one. Finally, in tumor-bearing mice ivermectin successfully reduced both tumor size and weight.

Conclusion:

Our results on the antitumor effects of ivermectin support its clinical testing.”

https://jeccr.biomedcentral.com/articles/10.1186/s13046-019-1251-7

“These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers.”