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]. IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment . For example, it was found in SK-MEL-28 melanoma cells that IVM can promote apoptosis as well as autophagy [74]. Column: Definitive study shows ivermectin is utterly useless against COVID-19. 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]. 2019 Jan;54(1):98-110. doi: 10.3892/ijo.2018.4604. 1 Two Major Areas Where Ivermectin is Proven to Fight Cancer Two critical and common areas that Ivermectin helps with are the following: Beneficial Area #1: Ivermectin and Apoptosis Apostosis is the technical term for programmed cell death. HSP27 is a molecular chaperone protein that is highly expressed in many cancers and associated with drug resistance and poor prognosis. 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. Bethesda, MD 20894, Web Policies Loibl S., Gianni L. HER2-positive breast cancer. A review of 10 random clinical trials, with more than 1,000 participants, also didn . " Within 2 or 3 days, nearly every single cancer cell died because they could not respond. 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. Bookshelf IVM activates glutamate-gated chloride channels in the parasite, causing a large amount of chloride ion influx and neuronal hyperpolarization, thereby leading to the release of gamma-aminobutyric acid (GABA) to destroy nerves, and the nerve transmission of muscle cells induces the paralysis of somatic muscles to kill parasites [9,10]. 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. Despite the large number of related studies, there are still some key issues that have not been resolved. 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 caspases–9/3. Choosing to participate in a study is an important personal decision. Jiang L., Wang P., Sun Y.J., Wu Y.J. IVM promotes degradation of PAK1 by ubiquitination/proteasome pathway, thereby inhibiting the Akt/mTOR signaling pathway. For general information, Learn About Clinical Studies. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. 1 For these indications, ivermectin has been widely used and is generally well-tolerated. It utilizes lysosomes to eliminate superfluous or damaged organelles in the cytoplasm to maintain homeostasis. IVM can inhibit the replication of flavivirus by targeting the NS3 helicase [17]; it also blocks the nuclear transport of viral proteins by acting on α/β-mediated nuclear transport and exerts antiviral activity against the HIV-1 and dengue viruses [18]. 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. RAS activation directly initiates PAK1, MAPK and PI3K/Akt pathway. Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of two‑dimensional similarity searching; the chemical structure of salinomycin was used as a query. Kibria G., Hatakeyama H., Harashima H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. The .gov means it’s official. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. ASC, Apoptosis-associated speck-like protein containing a CARD; ALCAR, acetyl-L-carnitine; CSCs, Cancer stem cells; DAMP, Damage-associated molecular pattern; EGFR, Epidermal growth factor receptor; EBV, Epstein-Barr virus; EMT, Epithelial mesenchymal-transition; GABA, Gamma-aminobutyric acid; GSDMD, Gasdermin D; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HER2, Human epidermal growth factor receptor 2; HMGB1, High mobility group box-1 protein; HSP27, Heat shock protein 27; LD50, median lethal dose; LDH, Lactate dehydrogenase; IVM, Ivermectin; MDR, Multidrug resistance; NAC, N-acetyl-L-cysteine; OCT-4, Octamer-binding protein 4; PAK1, P-21-activated kinases 1; PAMP, Pathogen-associated molecular pattern; PARP, poly (ADP- ribose) polymerase; P-gp, P-glycoprotein; PRR, pattern recognition receptor; ROS, Reactive oxygen species; STAT3, Signal transducer and activator of transcription 3; SID, SIN3-interaction domain; siRNA, small interfering RNA; SOX-2, SRY-box 2; TNBC, Triple-negative breast cancer; YAP1, Yes-associated protein 1, ivermectin(PubChem CID：6321424), avermectin(PubChem CID：6434889), selamectin(PubChem CID：9578507), doramectin(PubChem CID：9832750), moxidectin(PubChem CID：9832912). Ivermectin demonstrated an inhibitory effect upon the growth of MDA‑MB‑231 cells in the range of 0.2‑8 µM. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. In addition, characteristic pyroptosis phenomena such as cell swelling and rupturing were observed. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. In addition, morphological changed caused by apoptosis, including chromatin condensation, nuclear fragmentation, DNA fragmentation and apoptotic body formation were observed. Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. 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/β-catenin pathway. We found that the anticancer effect of ivermectin in combination with gemcitabine on pancreatic cancer is more effective than gemcitabine alone. Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. Epub 2014 Nov 18. 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 women’s cancers: a grand challenge in global health. Reduced tumorigenicity and drug resistance through the downregulation of octamer-binding protein 4 and Nanog transcriptional factor expression in human breast stem cells. In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion [65]. Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin. Epub 2018 Oct 24. Nevertheless, the list of anti cancer mechanisms related to Ivermectin is outstanding: Nagata S. Apoptosis and Clearance of Apoptotic Cells. Ivermectin is the top nonstandard drug for cancer, and it is better than many standard drugs approved by the medical establishment. The paper was eventually retracted by the medical journal that. 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. 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. 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. chief of breast surgery at the Karmanos Cancer Institute and . Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity [73]. Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. NCI CPTC Antibody Characterization Program. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. 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]. Eight studies had an open-label design, six were double-blind and placebo . Udensi U.K., Fagbenro-Beyioku A.F. Further studies showed that IVM could inhibit CSCs by regulating the PAK1-STAT3 axis [96]. It has a good effect on the treatment of parasitic diseases such as river blindness, elephantiasis, and scabies. Currently taking an angiotensin converting enzyme inhibitor (ACEi) or Angiotensin receptor blocker (ARB). Moreover, IVM could induce apoptosis of human brain microvascular endothelial cells and significantly inhibit angiogenesis. Cervical cancer is one of the most common gynecological malignancies, resulting in approximately 530,000 new cases and 270,000 deaths worldwide each year. Smit M.R., Ochomo E.O., Aljayyoussi G., Kwambai T.K., Abong’o 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. This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders. Kim J.H., Choi H.S., Kim S.L., Lee D.S. 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]. There are still some problems that need to be studied and resolved before IVM is used in the clinic. After more than 80 studies have evaluated the use of ivermectin, an antiparasitic medication, to treat or prevent COVID-19 in humans, the National Institutes of Health, the Centers for Disease. In addition, IVM shows potential for clinical application in asthma [20] and neurological diseases [21]. Geyer J., Gavrilova O., Petzinger E. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice. 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. The effects of ivermectin treatment on the expression of pluripotency and self‑renewal transcription factors, such as homeobox protein nanog (nanog), octamer‑binding protein 4 (oct‑4) and SRY‑box 2 (sox‑2), were evaluated by reverse transcription‑quantitative polymerase chain reaction and western blotting. The DDX23 helicase activity affects the expression of miR-12 [66]. 88]. The chemical structures of ivermectin and other avermectin family compounds in this review. 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. 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. The mechanism involved the inhibition by IVM of the Akt/mTOR pathway to induce autophagy and p-21-activated kinase 1(PAK1)was the target of IVM for breast cancer [32]. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. and transmitted securely. 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. The opposite pattern was observed with paclitaxel treatment. Cancer stem cells and self-renewal. Diehn M., Clarke M.F. Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment. In recent years, many new chemotherapeutic drugs have entered the clinic, but tumor cells are prone to drug resistance and obvious adverse reactions to these drugs. Nan Fang Yi Ke Da Xue Xue Bao. [Tricostantin A inhibits self-renewal of breast cancer stem cells in vitro]. Ivermectin: a potent new antiparasitic agent. IVM has been proven to significantly inhibit the proliferation and migration of HeLa cells and promote apoptosis [56]. Summary of the anticancer mechanism of IVM. Step #1: Ivermectin. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. Gasdermin D(GSDMD)is a substrate for activated caspase-1 and is considered to be a key protein in the execution of pyroptosis [86,87]. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Ivermectin has New Application in Inhibiting Colorectal Cancer Cell Growth Front Pharmacol. Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma. 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. Nappi's experiment also proved that IVM combined with erlotinib to achieved a synergistic killing effect by regulating EGFR activity and in HCC827 lung cancer cells [50]. In another study, IVM inhibited the proliferation of U251 and C6 glioma cells by inhibiting the Akt/mTOR pathway [64]. Authors Shican Zhou 1 , Hang Wu 1 , Wenjuan Ning 1 , Xiao Wu 1 , Xiaoxiao Xu 1 , Yuanqiao Ma 1 , Xingwang Li 1 , Junhong Hu 1 , Chenyu Wang 1 , Junpeng Wang 1 Affiliation The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. 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. Inflammasomes initiate the conversion of pro-caspase-1 via self-shearing into activated caspase-1. 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].
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ivermectin cancer study