It was also proven that IVM has a synergistic effect with cytarabine and daunorubicin on the treatment of leukemia. 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. Following the study, the FDA released a letter out of concern warning consumers not to self-medicate with ivermectin products intended for animals. 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]. HSP27 is a molecular chaperone protein that is highly expressed in many cancers and associated with drug resistance and poor prognosis. 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 [60]. MDR of tumor cells is the main cause of relapses and deaths after chemotherapy [97]. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. In addition, IVM could reduce the metastasis of lung cancer cells by inhibiting EMT. Ivermectin: a potent new antiparasitic agent. Ivermectin has been used off-label widely since the original in vitro study by Caly et al. The functionality is limited to basic scrolling. 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 . 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. Cervical cancer is one of the most common gynecological malignancies, resulting in approximately 530,000 new cases and 270,000 deaths worldwide each year. Guadalupe evaluated the effect of IVM on CSCs in the breast cancer cell line MDA-MB-231 [95]. 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 . . Gao A., Wang X., Xiang W., Liang H., Gao J., Yan Y. In short, the relationship between IVM-induced apoptosis and autophagy involves a complex regulatory mechanism, and the specific molecular mechanism needs further study. 4), but there is no specific evidence to prove this speculation. 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.". The article was . 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. 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. Interestingly, IVM could inhibit the expression of PAK1 protein but did not affect the expression of PAK1 mRNA [32].The proteasome inhibitor MG132 reversed the suppressive effect of IVM, which indicated that IVM mainly degraded PAK1 via the proteasome ubiquitination pathway. 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. The Prime Minister of Malaysia proclaimed a state of Emergency Ordinance on the 12th January 2021. Background: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. 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. Last. 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. HMGB1 is a chromatin protein present in all cells and its . 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 [29]. In addition, characteristic pyroptosis phenomena such as cell swelling and rupturing were observed. Dammann K., Khare V., Gasche C. Tracing PAKs from GI inflammation to cancer. 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]]. In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [[2], [3], [4], [5]] (Fig. Ivermectin is generally given with water on an empty stomach; however, administering ivermectin with food increases its bioavailability. This medicine is available only with your doctor's . 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. IVM can promote ROS release in cancer cells by P2 4/P2 7 receptors. A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma. Ivermectin is a minor cytochrome P450 3A4 substrate and a p-glycoprotein substrate. Effects of ivermectin on blood-feeding Phlebotomus papatasi, and the promastigote stage of Leishmania major. 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. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. Column: Definitive study shows ivermectin is utterly useless against COVID-19. Loibl S., Gianni L. HER2-positive breast cancer. 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]. By Laurie McGinley. 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. 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 January, the New York Post reported on a study of 573 patients that revealed only 8 who received Ivermectin died versus 44 out of 510 who passed away after being administered a placebo. 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. Retweets. 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]. Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. 36. Juarez M., Schcolnik-Cabrera A., Duenas-Gonzalez A. We believe that IVM can be further developed and introduced clinically as part of new cancer treatments in the near future. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of twodimensional similarity . Gewirtz D.A. IVM could significantly reduce the mitochondrial membrane potential and inhibit mitochondrial respiration and ATP production. On the one hand, activated caspase-1 induces the secretion of pro-inflammatory cytokines IL-1 and IL-18. This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. 88]. Deng F., Xu Q., Long J., Xie H. Suppressing ROSTFE3dependent autophagy enhances ivermectininduced apoptosis in human melanoma cells. A review of 10 random clinical trials, with more than 1,000 participants, also didn . Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug. As reported earlier, it may have anti-tumor, anti metastasis properties against some cancers. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. Rectal cancer. 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 1,553. In recent years, many studies have shown that autophagy is a double-edged sword in tumor development. Subsequently, NLRP3 Inflammasome initiates pro-caspase-1 to self-shear into mature caspase-1. 109,110]. The presence of the mitochondrial fuel acetyl-L-carnitine (ALCAR), and the antioxidant N-acetyl-L-cysteine (NAC), could reverse IVM-induced inhibition. Ivermectin, a potential anticancer drug derived from an antiparasitic drug. Animal studies with rats given 3 times the maximum recommended human dose of 200 mcg/kg did not show any . A global view of hepatocellular carcinoma: trends, risk, prevention and management. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs. Jan. 21, 2022 -- Doctors at Duke University are leading a national study to test whether three drugs could effectively treat COVID-19 including ivermectin . Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. 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. When the external environment is suitable, CSCs will rapidly proliferate to reactivate the formation and growth of tumors. Geyer J., Gavrilova O., Petzinger E. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice. IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment . 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]. PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Overall, IVM can induce autophagy through PAK1/Akt/mTOR pathway to represses the growth of cancer cells independent of apoptosis. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. IVM could inhibit the development of hepatocellular carcinoma by blocking YAP1 activity in spontaneous liver cancer Mob1b-/- mice [43].Cholangiocarcinoma is a malignant tumor that originates in the bile duct inside and outside the liver. But the BBC can reveal there are serious errors in a . IVM not only has strong effects on parasites but also has potential antiviral effects. In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion [65]. The four faces of autophagy: implications for cancer therapy. Jan 9, 2023. Targeting PAK1 is a novel and promising method for cancer treatment, and the development of PAK1 inhibitors has attracted widespread attention [111]. The reason for the proclamation was the rise in the number Despite the large number of related studies, there are still some key issues that have not been resolved. It included data from Surgisphere, a company that also provided inaccurate patient data . 15 Jan 2023 21:28:26 Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. 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]. 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