Last Updated on January 5, 2023 by Shaun Snapp. 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]. 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 [112] In addition, IVM has also been proven to show good permeability in tumor tissues [50]. 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. It is impossible to prove a negative, so the TOGETHER trial cannot prove that ivermectin is not useful in treating COVID. Zanconato F., Cordenonsi M., Piccolo S. YAP and TAZ: a signalling hub of the tumour microenvironment. already built in. Cellular ROS can activate NLRP3 Inflammasome including ASC, NLRP3 and pro-caspase-1 assemble. 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 [63]. Jan. 21, 2022 -- Doctors at Duke University are leading a national study to test whether three drugs could effectively treat COVID-19 including ivermectin . Computational searching of DrugBank, a database of approved drugs, was performed using the principles of twodimensional similarity . The chemical structures of ivermectin and other avermectin family compounds in this review. 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 recent years, many studies have shown that autophagy is a double-edged sword in tumor development. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. cancer, HIV or AIDS, . Rectal cancer. 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]. This is a randomized, doubled-blind and placebo-controlled phase II study that will evaluate the efficacy of the early use of ivermectin plus losartan in cancer patients who present with recent diagnosis of COVID-19. Kobayashi Y., Banno K., Kunitomi H., Tominaga E., Aoki D. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial Lim SCL, Hor CP, Tay KH, et al. It was also proven that IVM has a synergistic effect with cytarabine and daunorubicin on the treatment of leukemia. Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer. Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. In humans, the FDA has approved ivermectin to treat infections caused by some parasitic worms and, topically, for head lice and the skin disorder rosacea. 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. 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. We believe that IVM can be further developed and introduced clinically as part of new cancer treatments in the near future. describing ivermectin activity against SARS-CoV-2, 22 and in Brazil, in particular, the use of ivermectin . Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. However, whether ivermectin affects CRC is still unclear. Obviously, the existing results suggest that IVM-induced apoptosis and autophagy also exhibit cross talk. 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. 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. If you are pregnant, nursing, taking medication, or have a medical . However, there is no systematic and clear conclusion regarding the related molecular mechanism. As shown in Therefore, combination therapy is the most common method of chemotherapy. But the BBC can reveal there are serious errors in a . Degterev A., Yuan J. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. 108K. Views. A longitudinal study was undertaken in three hyperendemic foci in Mali and Senegal with 15 to 17 years of annual or six-monthly ivermectin treatment in order to assess residual levels of infection . The Prime Minister of Malaysia proclaimed a state of Emergency Ordinance on the 12th January 2021. Genetic and molecular epidemiology of adult diffuse glioma. In a previous article titled How Ivermectin Is Useful for Treating Cancer we covered the evidence for the benefits of Ivermectin for cancer. Juarez M., Schcolnik-Cabrera A., Duenas-Gonzalez A. Activated caspase-1 can cause pro-IL-1 and pro-IL-18 to mature and to be secreted. IVM has been proven to significantly inhibit the proliferation and migration of HeLa cells and promote apoptosis [56]. Hepatocellular carcinoma is the fourth leading cause of cancer death worldwide. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update. (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. IVM selectively inhibits the proliferation of tumors at a dose that is not toxic to normal cells and can reverse the MDR of tumors. A study published in the peer-reviewed American Journal of Therapeutics showed that the cost of ivermectin for other treatments in Bangladesh is around $0.60 to $1.80 for a five-day course. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itaja, a southern . The clinical trials described in this table are RCTs that had the greatest impact on the Panel's recommendation. The study was done by . 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. Quote Tweets. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. The FDA-approved drug . Overall, IVM can induce autophagy through PAK1/Akt/mTOR pathway to represses the growth of cancer cells independent of apoptosis. 1 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. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. 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 article, "Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen," is a review of various studies on the antiviral effects of ivermectin. Ashour D.S. Received 2020 Jun 5; Revised 2020 Sep 11; Accepted 2020 Sep 11. Methods We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 . Avermectin family drugs such as selamectin [36,41,113], and doramectin [114] also have anticancer effects, as previously reported. Background Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. An experiment found that IVM could significantly enhance the inhibitory effects of erlotinib and cetuximab on lung cancer and colorectal cancer [50]. (Ub:Ubiquitination, P:Phosphorylation). 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 [[90], [91], [92]]. 64,74]. Subsequently, the inactivation Akt/mTOR signaling cannot inhibit the formation of the Beclin-1 complex, thus inducing the formation autophagosome. A word about safety There were no serious ivermectin-related adverse events. Last. Gao A., Wang X., Xiang W., Liang H., Gao J., Yan Y. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. Retweets. In animals, it is used as a deworming . Kircik L.H., Del Rosso J.Q., Layton A.M., Schauber J. 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]. In a study that . A Colombian health worker . 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. 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 [1]. Following the study, the FDA released a letter out of concern warning consumers not to self-medicate with ivermectin products intended for animals. 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. In another study, IVM inhibited the proliferation of U251 and C6 glioma cells by inhibiting the Akt/mTOR pathway [64]. A global view of hepatocellular carcinoma: trends, risk, prevention and management. 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. Moreover, Akt can inhibit -catenin transfer into nucleus. 5). The study was conducted on 18 rectal cancer patients at Memorial Sloan Kettering Cancer Center in Manhattan and had a 100 percent success rate, according to a paper published Sunday in the New . It has a good effect on the treatment of parasitic diseases such as river blindness, elephantiasis, and scabies. 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) [37]. Relatively safe. 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 aim of the present study was to demonstrate that ivermectin preferentially inhibited cancer stemlike cells (CSC) in breast cancer cells and downregulated the expression of 'stemness' genes. 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. 1-26 However, those studies have limitations that make them less definitive and informative than the studies summarized in the table. 36. Later in December, FLCCC founder Paul Marik, the first author on the now-rejected Frontiers manuscript and a professor at Eastern Virginia Medical School, wrote a paper reviewing ivermectin that included references to debunked papers, including an observational study of ivermectin in COVID-19 patients led by now-discredited Surgisphere Corporation. Two studied the effects of intensive physical treatment plus selenium or placebo in preventing AIE's, and two studied the effects of Ivermectin, Diethylcarbamazine (DEC) (anti-filarial agents) and penicillin as prophylactic treatment for adeno lymphangitis(ADL) versus placebo.Both selenium trials reported no inflammatory episodes during the . Despite the fact that these trials found ivermectin inferior to the cream it was being tested against, it still won approval due to its low cost and ease of administration. Diehn M., Clarke M.F. The presence of the mitochondrial fuel acetyl-L-carnitine (ALCAR), and the antioxidant N-acetyl-L-cysteine (NAC), could reverse IVM-induced inhibition. 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. 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 [[78], [79], [80], [81]]. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. Top medical journals have rejected a paper about the study, and its main author, Flavio Cadegiani, an endocrinologist at the biotech company Applied Biology, has previously touted unproven COVID-19 medications, such as ivermectin, azithromycin, and antiworm compounds. Deng F., Xu Q., Long J., Xie H. Suppressing ROSTFE3dependent autophagy enhances ivermectininduced apoptosis in human melanoma cells. aAnhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui Province 233030, China, bClinical Medical Department, Bengbu Medical College, Bengbu, Anhui Province 233030, China, cDepartment of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui Province 233030, China, dDepartment of Microbiology and Parasitology, Bengbu Medical College, Bengbu, Anhui Province 233030, China, eSchool of Fundamental Sciences, Bengbu Medical College, Bengbu, Anhui Province 233030, China. 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. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. p21-activated kinases in cancer. . OBrien C.A., Kreso A., Jamieson C.H. Abstract. 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]. 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. Ivermectin: a potent new antiparasitic agent. After treatment with IVM, the proliferation of multiple breast cancer cell lines including MCF-7, MDA-MB-231 and MCF-10 was significantly reduced. MDR of tumor cells is the main cause of relapses and deaths after chemotherapy [97]. Bishop B.F., Bruce C.I., Evans N.A., Goudie A.C., Gration K.A., Gibson S.P., Pacey M.S., Perry D.A., Walshe N.D., Witty M.J. Selamectin: a novel broad-spectrum endectocide for dogs and cats. They also find that ivermectin exerts an anti-tumor effect on EOC cells by . Most of the anticancer research performed on the avermectin family has been focused on avermectin and IVM until now. IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. 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. 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. Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. 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 [95]. 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. April 8, 2021 at 8:00 a.m. EDT. 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. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. This group explores and celebrates the successes of the repurposed drug Fenbendazole to help with cancer treatment. Animal studies with rats given 3 times the maximum recommended human dose of 200 mcg/kg did not show any . The four faces of autophagy: implications for cancer therapy. In addition, there is also no clinically applicable therapeutic drug currently [34,35]. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. Mingyang Tang, Xiaodong Hu, [], and Qiang Fang. Cancer Treatment. The article was . 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]. Moreover, IVM could induce apoptosis of human brain microvascular endothelial cells and significantly inhibit angiogenesis. We believe that deeper exploration of the mechanism can further guide the use of IVM in the treatment of cancer. 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. Cancer cells exposure to IVM can be induced to generate ROS generation and reduce membrane potential of mitochondria. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. We are experimenting with display styles that make it easier to read articles in PMC. It is highly effective against many microorganisms including some viruses. Earlier, we mentioned the role of IVM in docetaxel-resistant prostate cancer [50] and gemcitabine-resistant cholangiocarcinoma [44]. However, to date, no exact target for IVM action has been found. . In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion [65]. 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. 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.