However, to date, no exact target for IVM action has been found. 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]. Second, IVM seems to induce mixed cell death in tumor cells, which is also a controversial issue. However, whether ivermectin affects CRC is still unclear. In short, the relationship between IVM-induced apoptosis and autophagy involves a complex regulatory mechanism, and the specific molecular mechanism needs further study. PAK1 allocates crosstalk between the PI3K and MAPK pathways. This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. 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]. Ivermectin, a potential anticancer drug derived from an antiparasitic drug. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. 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. Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. Melanoma is the most common malignant skin tumor with a high mortality rate. 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. 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. This was related to the induction of mitochondrial dysfunction and oxidative stress. Cervical cancer is one of the most common gynecological malignancies, resulting in approximately 530,000 new cases and 270,000 deaths worldwide each year. Avermectin family drugs such as selamectin [36,41,113], and doramectin [114] also have anticancer effects, as previously reported. ). Prichard R.K., Geary T.G. 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]. In a study published in the journal Oncotarget on July 6, Gregory Riggins, M.D., Ph.D., professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine, and his team used two different mouse models to determine that the anti-parasitic drug mebendazole could slow or stop the growth and spread of both early and late-stage pancreatic cancer. Therefore, combination therapy is the most common method of chemotherapy. Gong T., Liu L., Jiang W., Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Antoszczak M., Markowska A., Markowska J., Huczynski A. This group explores and celebrates the successes of the repurposed drug Fenbendazole to help with cancer treatment. Mingyang Tang, Xiaodong Hu, [], and Qiang Fang. (4) IVM can enhance the sensitivity of chemotherapeutic drugs and reduce the production of resistance. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. Ivermectin has been used off-label widely since the original in vitro study by Caly et al. The inflammasome is a multimolecular complex containing pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. 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. Old wine in new bottles: Drug repurposing in oncology. The present study represents the first study evaluating the anticancer efficacy of ivermectin in pancreatic cancer. IVM could block the cell cycle and induce cell apoptosis through a KPNB1-dependent mechanism in ovarian cancer [59]. This included: a laboratory study showing that the drug acted as a strong antiviral in a petri dish, a study in a French nursing home where the residents took ivermectin to treat a scabies . A global view of hepatocellular carcinoma: trends, risk, prevention and management. IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. 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. 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. The FDA has not authorized or approved ivermectin for use in preventing or treating COVID-19 in humans or animals. treatment [[23], [24], [25], [26], [27]]. Expansion and evolution of cell death programmes. Dr. Mercola encourages you to make your own health care decisions based upon your research and in partnership with a qualified health care professional. 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]. Ashour D.S. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. 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. 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. Emerging Role of Circulating Tumor Cells in Gastric Cancer. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. We use cookies to enhance your experience. Programmed cell death mediated by autophagy after IVM intervention and the enhancement of the anticancer efficacy of IVM by regulating autophagy are interesting topics. But the BBC can reveal there are serious errors in a . Genetic and molecular epidemiology of adult diffuse glioma. Background Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. It was also proven that IVM has a synergistic effect with cytarabine and daunorubicin on the treatment of leukemia. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. 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. 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]. Since the first report that IVM could reverse tumor multidrug resistance (MDR) in 1996 [22], a few relevant studies have emphasized the potential use of IVM as a new cancer. Recognition of the role of Natural Products as drugs to treat neglected tropical diseases by the 2015 Nobel prize in physiology or medicine. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. Pyroptosis is a type of inflammatory cell death induced by inflammasomes. The study was published January 10, 2022 in Clinical Cancer Research. The Prime Minister of Malaysia proclaimed a state of Emergency Ordinance on the 12th January 2021. 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 . As reported earlier, it may have anti-tumor, anti metastasis properties against some cancers. In addition, morphological changed caused by apoptosis, including chromatin condensation, nuclear fragmentation, DNA fragmentation and apoptotic body formation were observed. Wang J., Xu Y., Wan H., Hu J. 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. RAS activation directly initiates PAK1, MAPK and PI3K/Akt pathway. Wen P.Y., Kesari S. Malignant gliomas in adults. 88]. IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment . Liu J., Zhang K., Cheng L., Zhu H., Xu T. Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin. 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. Cellular ROS can activate NLRP3 Inflammasome including ASC, NLRP3 and pro-caspase-1 assemble. The functionality is limited to basic scrolling. PAK1 cross regulate multiple signal pathways. Intuyod's experiment found that IVM inhibited the proliferation of KKU214 cholangiocarcinoma cells in a dose- and time-dependent manner [44]. 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]. Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity [73]. 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. Obviously, the existing results suggest that IVM-induced apoptosis and autophagy also exhibit cross talk. Nasopharyngeal carcinoma is a malignant tumor derived from epithelial cells of the nasopharyngeal mucosa. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. 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]. Importantly, IVM is an established drug used for the treatment of parasitic diseases such as river blindness and elephantiasis. The excessive activation of PAK1 is involved in the formation, development, and invasion of various cancers [ 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. 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. . Recently scientists have discovered that IVM has a strong anticancer effect. IVM induces different programmed cell death patterns in different tumor cells (Table 1). Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. 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]. 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. p21-activated kinases in 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. 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