Harbeck N., Penault-Llorca F., Cortes J., Gnant M., Houssami N., Poortmans P., Ruddy K., Tsang J., Cardoso F. Breast cancer. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. Mingyang Tang, Xiaodong Hu, [], and Qiang Fang. Yang J.D., Hainaut P., Gores G.J., Amadou A., Plymoth A., Roberts L.R. Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. And to many, the claims simply seem implausible. 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. 64,74]. IVM regulates the tumor microenvironment and mediates immunogenic cell death, which may be a new direction for research exploring anticancer mechanisms in the future. However, whether ivermectin affects CRC is still unclear. Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. You may switch to Article in classic view. Despite the large number of related studies, there are still some key issues that have not been resolved. 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 [104]. Pouliot J.F., LHeureux F., Liu Z., Prichard R.K., Georges E. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Smit M.R., Ochomo E.O., Aljayyoussi G., Kwambai T.K., Abongo 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. The study was published January 10, 2022 in Clinical Cancer Research. Effects of ivermectin on blood-feeding Phlebotomus papatasi, and the promastigote stage of Leishmania major. Crump A. Ivermectin: enigmatic multifaceted wonder drug continues to surprise and exceed expectations. 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 [40]. Most of the anticancer research performed on the avermectin family has been focused on avermectin and IVM until now. Relatively safe. P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders. 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]. Therefore, continued study and testing of safe and effective combination drug therapies is essential to maximize the anticancer effects of IVM. But the BBC can reveal there are serious errors in a . The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. 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. However, the exact molecular target of IVM that affects the Wnt/-catenin pathway remains to be explored. The authors report no declarations of interest. 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. The ePub format is best viewed in the iBooks reader. This study to examine ivermectin, as well as a few other current medications to gauge their effectiveness against COVID-19, goes by the name of ACTIV-6. 36. The Panel reviewed other clinical studies of IVM for the treatment of COVID-19. 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. 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 [32]. Last. Earlier, we mentioned that IVM combined with conventional chemotherapeutic drugs such as cisplatin [60], paclitaxel [59], daunorubicin and cytarabine [51], or with targeted drugs such as dasatinib [53] and dapafenib [73] shows great potential for cancer treatment. Moreover, Akt can inhibit -catenin transfer into nucleus. Existing research is sufficient to demonstrate the great potential of IVM and its prospects as a novel promising anticancer drug after additional research. PAK1 cross regulate multiple signal pathways. Franklin K.M., Asatryan L., Jakowec M.W., Trudell J.R., Bell R.L., Davies D.L. Kircik L.H., Del Rosso J.Q., Layton A.M., Schauber J. It works by interfering with the nerve and muscle functions of worms, by paralyzing and killing them. 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. However, to date, no exact target for IVM action has been found. Ashour D.S. treatment [[23], [24], [25], [26], [27]]. Glioblastoma is the deadliest glioma, with a median survival time of only 14-17 months [61,62]. 1,553. The combination of drugs can effectively increase efficacy, reduce toxicity or delay drug resistance. Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. When they compared the excluded ivermectin group of 75 to the remaining 198 subjects in the placebo groups, ivermectin reduced SP 9.3% vs. 21.2%. 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. Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. Marino G., Niso-Santano M., Baehrecke E.H., Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. 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. Finally, activated PARP and caspase-3 trigger apoptosis. 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. 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. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of twodimensional similarity . The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation. The incidence is obviously regional and familial, and Epstein-Barr virus (EBV) infection is closely related [68]. Introduction. Further studies showed that IVM could inhibit CSCs by regulating the PAK1-STAT3 axis [96]. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. Pyroptosis is a type of inflammatory cell death induced by inflammasomes. There are still some problems that need to be studied and resolved before IVM is used in the clinic. Kumar R., Li D.Q. 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. Therefore, we believe that the anticancer effect of IVM is not limited to cytotoxicity, but also involves the regulation of the tumor microenvironment. 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 [82]. describing ivermectin activity against SARS-CoV-2, 22 and in Brazil, in particular, the use of ivermectin . On the other hand, caspase-1 activated by GSDMD triggers pyroptosis independent of apoptosis. 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/-catenin pathway. After treatment with IVM, the proliferation of multiple breast cancer cell lines including MCF-7, MDA-MB-231 and MCF-10 was significantly reduced. 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. 1-26 However, those studies have limitations that make them less definitive and informative than the studies summarized in the table. Geyer J., Gavrilova O., Petzinger E. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice. As mentioned above, the anticancer mechanism of IVM involves a wide range of signaling pathways such as Wnt/-catenin, Akt/mTOR, MAPK and other possible targets such as PAK1 and HSP27, as well as other mechanisms of action (Table 2 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. The article was . 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. Overall, IVM can induce autophagy through PAK1/Akt/mTOR pathway to represses the growth of cancer cells independent of apoptosis. In addition, IVM shows potential for clinical application in asthma [20] and neurological diseases [21]. The study found that there was no difference in hospitalization rates between patients who received placebo and those who received ivermectin. Diehn M., Clarke M.F. Ivermectin, an antiparasitic drug, has been shown to possess anti-inflammation, anti-virus, and antitumor properties. 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. 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. Types of Cancer Treatment; Side Effects of Cancer Treatment; Clinical Trials Information. Campbell W.C., Fisher M.H., Stapley E.O., Albers-Schonberg G., Jacob T.A. What this study does and does not show. 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. Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. Approximately 80% of cases of liver cancer are caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection [42]. Cellular ROS can activate NLRP3 Inflammasome including ASC, NLRP3 and pro-caspase-1 assemble. A study published in this week's Journal of the American Medical Association ( JAMA) reported on a double-blind placebo controlled randomized trial of nearly 1600 adults with mild to moderate . 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. Ivermectin can turn "cold" breast tumors "hot" We studied the effects of ivermectin in vivo using the 4T1 mouse model of TNBC. 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. Targeting autophagy in cancer. Gallardo F., Mariam B., Gence R., Tilkin-Mariam A.-F. Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth. But ivermectin is not a miracle cure for COVID-19, and there's no . Huang Z., Wu T., Liu A.Y., Ouyang G. Differentiation and transdifferentiation potentials of cancer stem cells. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. Biochemical and Biophysical Research Communications. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients. Tracey Savich, owner of Rolling Hills General Store, felt the need to warn customers against using veterinary . Lung cancer has the highest morbidity and mortality among cancers [70]. p21-activated kinases in cancer. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. Patel H., Yacoub N., Mishra R., White A., Long Y., Alanazi S., Garrett J.T. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Formulated as a lotion, ivermectin is safe enough to be administered as an over-the-counter treatment for head lice in kids. The FDA first issued a warning in April 2020 that ivermectin intended for use in animals should not be used to treat COVID-19 . IVM selectively inhibits the proliferation of tumors at a dose that is not toxic to normal cells and can reverse the MDR of tumors. Nasopharyngeal carcinoma is a malignant tumor derived from epithelial cells of the nasopharyngeal mucosa. 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]]. . The following side effects and drug interactions that can occur with ivermectin are signs of ivermectin toxicity, according to the CDC: Abdominal pain, nausea, vomiting, and diarrhea; Dizziness; Low blood pressure; Tachycardia (an abnormally fast heart rate) Headache; Blurred vision and visual hallucinations; Confusion Wen P.Y., Kesari S. Malignant gliomas in adults. ). 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. Summary of the anticancer mechanism of IVM. 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. 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]. (Ub:Ubiquitination, P:Phosphorylation). 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 . 4), but there is no specific evidence to prove this speculation. Ivermectin: a potent new antiparasitic agent. 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. Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment? ). IVM halted the cell cycle in S phase and promoted apoptosis. The ACTIV-6 study enrolled 1,800 participants. 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. I take small doses of 6-12 mg regularly (3-4 x/week) after reading about it at NIH.gov, which someone else has now posted. Autophagy-Independent Functions of the Autophagy Machinery. 1 Goudie A.C., Evans N.A., Gration K.A., Bishop B.F., Gibson S.P., Holdom K.S., Kaye B., Wicks S.R., Lewis D., Weatherley A.J. Abstract. 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. A Colombian health worker . Find NCI-Supported Clinical Trials; What Are Clinical Trials? IVM could block the cell cycle and induce cell apoptosis through a KPNB1-dependent mechanism in ovarian cancer [59]. Ivermectin (Systemic - Last updated on December 12, 2022 All rights owned and reserved by Memorial Sloan Kettering Cancer Center. IVM not only has strong effects on parasites but also has potential antiviral effects. Written by Carolyn Crist. We are experimenting with display styles that make it easier to read articles in PMC. A recent double-blind randomized study in Cali, Colombia found that ivermectin, used among adults with mild cases of COVID-19, "did not significantly improve the time to resolution of symptoms . Jan 9, 2023. 2 This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. 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. HMGB1 is a chromatin protein present in all cells and its . Markowska A., Kaysiewicz J., Markowska J., Huczynski A. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. The reason for the proclamation was the rise in the number However, NAC reversed the effect of IVM, which indicated that IVM increased TFE3-dependent autophagy through the ROS signaling pathway. Here's What You Need to Know about Ivermectin. If you are pregnant, nursing, taking medication, or have a medical . Pancreatic cancer is an aggressive cancer characterized by high mortality and poor prognosis with survival of less than 5 years when advanced. Kumar R., Gururaj A.E., Barnes C.J. (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. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. On the one hand, activated caspase-1 induces the secretion of pro-inflammatory cytokines IL-1 and IL-18. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. Where are the tablets available without prescription? EverythingIsFine . 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. Today, ivermectin is being increasingly used worldwide to combat other diseases in humans, such as Strongyloidiasis (which infects some 35 million each year), scabies (which causes 300 million cases annually), Pediculosis, Gnathostomiasis and Myiasisand new and promising properties and uses for ivermectin and other avermectin derivatives are . Likes. Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Intuyod's experiment found that IVM inhibited the proliferation of KKU214 cholangiocarcinoma cells in a dose- and time-dependent manner [44]. Importantly, IVM is an established drug used for the treatment of parasitic diseases such as river blindness and elephantiasis. Only the paste. The inflammasome is a multimolecular complex containing pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. . 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. However, in special circumstances, autophagy may also help to induce apoptosis or necrosis [83]. Gong T., Liu L., Jiang W., Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. In the past year, more than one million patients with gastric cancer have been diagnosed worldwide [38]. Levy J.M.M., Towers C.G., Thorburn A. 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. Generating an ePub file may take a long time, please be patient. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. Several studies showed that the ivermectin has antitumor effects on a variety of cancer cells. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. We believe that IVM can be further developed and introduced clinically as part of new cancer treatments in the near future. In addition, PAK1 facilitates Wnt/-catenin signaling, make -catenin accumulate in the cytoplasm and translocate to the nucleus. Deepak K.G.K., Vempati R., Nagaraju G.P., Dasari V.R., N. S, Rao D.N., Malla R.R. Expansion and evolution of cell death programmes. Kobayashi Y., Banno K., Kunitomi H., Tominaga E., Aoki D. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Views. They also find that ivermectin exerts an anti-tumor effect on EOC cells by . 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. 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]. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Wang J., Seebacher N., Shi H., Kan Q., Duan Z. Our scientists pursue every aspect of cancer researchfrom exploring the biology of genes and cells, to developing immune-based treatments, uncovering the causes of metastasis, and more. Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. 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. 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 [53]. Ivermectin is an anti-parasite medication used to treat a variety of parasitic diseases such as parasitic worms, hookworm and whipworm. Ivermectin, a potential anticancer drug derived from an antiparasitic drug. Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment . JAMA Internal Medicine February 18, 2022. In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Therefore, combination therapy is the most common method of chemotherapy. 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. ). Siegel R.L., Miller K.D., Jemal A. This group explores and celebrates the successes of the repurposed drug Fenbendazole to help with cancer treatment. 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. Programmed cell death mediated by autophagy after IVM intervention and the enhancement of the anticancer efficacy of IVM by regulating autophagy are interesting topics. It is considered as a new target for cancer therapy [107]. 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. An NIH trial may settle debate over ivermectin; officials warn people not to take animal formulation of the drug. 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. 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. As reported earlier, it may have anti-tumor, anti metastasis properties against some cancers. The study found that patients with Covid-19 treated in hospital who "received ivermectin early reported substantial recovery" and that there was "a substantial improvement and reduction in . Wang J., Xu Y., Wan H., Hu J. 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 [49]. 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. 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. As the cost of the research and development of new anticancer drugs continues to increase, drug repositioning has become increasingly important. Jan. 21, 2022 -- Doctors at Duke University are leading a national study to test whether three drugs could effectively treat COVID-19 including ivermectin . 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]. The 5-year survival rate after diagnosis is approximately 47% [27,57]. These results indicated the significance of applying IVM for the treatment of chemotherapy patients with MDR. The phenomenon of IVM-induced autophagy has also been reported in glioma and melanoma [ The authors speculated that IVM may mediate the occurrence of pyroptosis via the P2 4/P2 7/NLRP3 pathway (Fig. The drug, Ivermectin, an antiparasitic medicine, is an inhibitor of the virus SARS-CoV-2 in-vitro and can effectively cause a reduction in virus at 48 hours in cell cultures. In mid-2020, an ivermectin study published in the prestigious New England Journal of Medicine was retracted. A few weeks ago, William C. Campbell and Satoshi Omura, the scientists who developed ivermectin, won a Nobel Prize for the research that led to development of the drug, which has vastly reduced . Arcangeli S., Pinzi V., Arcangeli G. Epidemiology of prostate cancer and treatment remarks. It was based on a very small flawed 2002 study mentioned in a 2011 study. Animal studies with rats given 3 times the maximum recommended human dose of 200 mcg/kg did not show any . This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. In addition, there is also no clinically applicable therapeutic drug currently [34,35]. Avermectin family drugs such as selamectin [36,41,113], and doramectin [114] also have anticancer effects, as previously reported. IVM could significantly reduce the mitochondrial membrane potential and inhibit mitochondrial respiration and ATP production. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. It included data from Surgisphere, a company that also provided inaccurate patient data . A study actually a review of trials done with ivermectin on COVID-19 patients claims large reductions in COVID-19 deaths are "possible using ivermectin.". Satoshi mura 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. The excessive activation of PAK1 is involved in the formation, development, and invasion of various cancers [ 5. Ivermectin is a minor cytochrome P450 3A4 substrate and a p-glycoprotein substrate. This suggests that ivermectin may be an anticancer drug with great potential. Recognition of the role of Natural Products as drugs to treat neglected tropical diseases by the 2015 Nobel prize in physiology or medicine. 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. We formerly reported that the combination of dichloroacetate, omeprazole, and tamoxifen blocked cancer progression by reducing lactic acid production and inducing superoxide production. Loibl S., Gianni L. HER2-positive breast cancer. IVM has also shown beneficial effects against other parasitic diseases, such as malaria [11,12], trypanosomiasis [13], schistosomiasis [14], trichinosis [15] and leishmaniasis [16]. EOC is the fifth leading cause of cancer-related deaths in women and has a particularly grim outlook upon diagnosis. Received 2020 Jun 5; Revised 2020 Sep 11; Accepted 2020 Sep 11. It is highly effective against many microorganisms including some viruses. 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. 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. It is impossible to prove a negative, so the TOGETHER trial cannot prove that ivermectin is not useful in treating COVID. 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 . Moreover, IVM can up-regulate Bax and down-regulate Bcl-2, promote releasing of cytochrome C into the cytosol, and activate the signaling cascade of caspases9/3. The chemical structures of ivermectin and other avermectin family compounds in this review. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. However, there is no systematic and clear conclusion regarding the related molecular mechanism. 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]. Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity [73]. An early study using cells in petri dishes suggested that ivermectin has antiviral properties at very high concentrations and could inhibit the pandemic coronavirus, SARS-CoV-2. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. 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. 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 /-mediated nuclear transport and exerts antiviral activity against the HIV-1 and dengue viruses [18]. Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. It . 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 [37]. Prichard R.K., Geary T.G. 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. Genetic and molecular epidemiology of adult diffuse glioma. 3). Epigenetic therapy for ovarian cancer: promise and progress. 672. 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. 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]. 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 [ WASHINGTON Ivermectin, a controversial drug used commonly as a horse dewormer as well as a treatment for parasitic infections in humans, could be capable of treating COVID-19 patients and potentially ending the pandemic, some scientists claim.The team of researchers, including three U.S. government senior scientists, are calling for governments around the world to start treating . Ivermectin: From theory to clinical application. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. We found that IVM inhibits tumor cell development in a PAK1-dependent manner in most cancers. Rectal cancer. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. The study was done by . The study group included adult patients from 12 cities throughout Brazil, where ivermectin has been widely embraced and utilized since the early months of the pandemic. IVM could inhibit the DDX23/miR-12 signaling pathway by affecting the activity of DDX23 helicase, thereby inhibiting malignant biological behaviors. On average, a new case is diagnosed every 18 seconds worldwide [30,31]. A study published in JAMA Network this month estimated private and Medicare plans may have paid nearly $2.5 million for ivermectin prescriptions in the week of Aug. 13 alone. Summary of IVM promotes programmed cell death. 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). Nambaras 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]. Inflammasomes initiate the conversion of pro-caspase-1 via self-shearing into activated caspase-1. 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]. 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 womens cancers: a grand challenge in global health. Gastric cancer is one of the most common malignant tumors worldwide. Doramectin--a potent novel endectocide. 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. 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]. 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. However, whether ivermectin affects CRC is still unclear. Background: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update. Draganov D., Gopalakrishna-Pillai S., Chen Y.R., Zuckerman N., Moeller S., Wang C., Ann D., Lee P.P. IVM has been proven to significantly inhibit the proliferation and migration of HeLa cells and promote apoptosis [56]. In addition, IVM could reduce the metastasis of lung cancer cells by inhibiting EMT. A new study evaluated the effect of ivermectin on time to recovery from coronavirus disease 2019 (COVID-19) in patients with mild to moderate disease. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. 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. 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. RAS activation directly initiates PAK1, MAPK and PI3K/Akt pathway. IVM induces different programmed cell death patterns in different tumor cells (Table 1). 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 [22]. This was related to the induction of mitochondrial dysfunction and oxidative stress. Hence several favorable signals were detected in a study with several structural biases against ivermectin. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. 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. The ePub format uses eBook readers, which have several "ease of reading" features Subsequently, NLRP3 Inflammasome initiates pro-caspase-1 to self-shear into mature caspase-1. Elsevier Public Health Emergency Collection, HelaColorectal cancer (CC14, CC36, DLD1,Ls174 T)Ovarian cancer (SKOV3, OVCAR3, CAOV3)Renal cell carcinoma (SW-839, Caki-2, 786-O, A498, ACHN)Leukemia(K562, primary CD34, Glioma (U251, C6)Breast cancer(MCF-7, MDA-MB-231)Melanoma (SK-MEL-28), Breast cancer, Ovarian cancer, Nasopharyngeal carcinoma, Melanoma, Prostate cancer, Lung cancer Colorectal cancer. Yoshida G.J. A large, randomized study of COVID-19 patients in Brazil shows that being treated with ivermectin has little or no benefit. A clinical trial of 476 patients found ivermectin didn't improve the recovery time in patients who had COVID-19. 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 [108]. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. 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. The discoverers of IVM, Japanese scientist Satoshi mura and Irish scientist William C. Campbell, won the Nobel Prize in Physiology or Medicine in 2015 [7,8]. Giving ivermectin with balstilimab may increase the effect of balstilimab in shrinking tumors in patients with triple negative breast cancer. Juarez M., Schcolnik-Cabrera A., Duenas-Gonzalez A. The clinical trials described in this table are RCTs that had the greatest impact on the Panel's recommendation. Retweets. Galluzzi L., Green D.R. Melanoma is the most common malignant skin tumor with a high mortality rate. 88]. 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. 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. It is intended as a sharing of knowledge and information from the research and experience of Dr. Mercola and his community. Drug repositioning is a shortcut to accelerate the development of anticancer drugs. Autophagy is a lysosomal-dependent form of programmed cell death. Moufarrij S., Dandapani M., Arthofer E., Gomez S., Srivastava A., Lopez-Acevedo M., Villagra A., Chiappinelli K.B. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [[101], [102], [103]]. 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. Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment. The FDA-approved drug . Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. 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. Last Updated on January 5, 2023 by Shaun Snapp. Ivermectin is used to treat river blindness (onchocerciasis), intestinal infection from threadworms (strongyloidiasis), and other kinds of worm infections. IVM promotes degradation of PAK1 by ubiquitination/proteasome pathway, thereby inhibiting the Akt/mTOR signaling pathway. . Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. The latest research shows that in normal circumstances autophagy will prevent the induction of apoptosis and apoptosis-related caspase enzyme activation will inhibit autophagy. Ivermectin has been used off-label widely since the original in vitro study by Caly et al. Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug. When the external environment is suitable, CSCs will rapidly proliferate to reactivate the formation and growth of tumors. 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. Han S.J., Lovaszi M., Kim M., DAgati V., Hasko G., Lee H.T. The DDX23 helicase activity affects the expression of miR-12 [66]. 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). It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. 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. 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. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. 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. Dammann K., Khare V., Gasche C. Tracing PAKs from GI inflammation to cancer. OBrien C.A., Kreso A., Jamieson C.H. Ivermectin neither reduced hospital admissions for worsening COVID-19 nor shortened the time that infected patients spent in the emergency room, according to data from a large randomized . Subsequently, the inactivation Akt/mTOR signaling cannot inhibit the formation of the Beclin-1 complex, thus inducing the formation autophagosome. 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]. For example, it was found in SK-MEL-28 melanoma cells that IVM can promote apoptosis as well as autophagy [74]. Abstract. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43].
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