The inflammasome is a multimolecular complex containing pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. 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. RAS activation directly initiates PAK1, MAPK and PI3K/Akt pathway. 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. 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. We use cookies to enhance your experience. 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 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]. 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. 5). 5. Relatively safe. Expansion and evolution of cell death programmes. 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). Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [[101], [102], [103]]. 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]. 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. We found that the anticancer . HSP27 is a molecular chaperone protein that is highly expressed in many cancers and associated with drug resistance and poor prognosis. Ivermectin can turn "cold" breast tumors "hot" We studied the effects of ivermectin in vivo using the 4T1 mouse model of TNBC. 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]. Gong T., Liu L., Jiang W., Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. 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. 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. Autophagy is a lysosomal-dependent form of programmed cell death. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. Yoshida G.J. PAK1 allocates crosstalk between the PI3K and MAPK pathways. 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. Rectal cancer. Zheng Z., Li G. Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer. It . Cancer statistics, 2019. 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. On the one hand, activated caspase-1 induces the secretion of pro-inflammatory cytokines IL-1 and IL-18. But the study provides solid evidence that ivermectin is no better than a placebo when given at a dose of roughly 30 milligrams per day over a three-day interval. Deng F., Xu Q., Long J., Xie H. Suppressing ROSTFE3dependent autophagy enhances ivermectininduced apoptosis in human melanoma cells. Second, IVM seems to induce mixed cell death in tumor cells, which is also a controversial issue. Pyroptosis is a type of inflammatory cell death induced by inflammasomes. 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. Therefore, CSCs have been widely recognized as the main cause of recurrence after treatment [93,94]. However, here, we must emphasize that because IVM cannot effectively pass the blood-brain barrier [67], the prospect of the use of IVM in the treatment of gliomas is not optimistic. EOC is the fifth leading cause of cancer-related deaths in women and has a particularly grim outlook upon diagnosis. Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update. Therefore, continued study and testing of safe and effective combination drug therapies is essential to maximize the anticancer effects of IVM. 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. IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. Effects of ivermectin on blood-feeding Phlebotomus papatasi, and the promastigote stage of Leishmania major. Dammann K., Khare V., Gasche C. Tracing PAKs from GI inflammation to cancer. Its morbidity has increased by an average of 2% annually worldwide and the clinical treatment effect is not satisfactory [[45], [46], [47]]. 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]. 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. Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., Dewhirst M.W., Bigner D.D., Rich J.N. As the cost of the research and development of new anticancer drugs continues to increase, drug repositioning has become increasingly important. Here's What You Need to Know about Ivermectin. McKerrow J.H. HMGB1 is a chromatin protein present in all cells and its . Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. Diana A., Carlino F., Franzese E., Oikonomidou O., Criscitiello C., De Vita F., Ciardiello F., Orditura M. Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes. 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. We are experimenting with display styles that make it easier to read articles in PMC. Ivermectin is used to treat river blindness (onchocerciasis), intestinal infection from threadworms (strongyloidiasis), and other kinds of worm infections. 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. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation. The authors report no declarations of interest. Hepatocellular carcinoma is the fourth leading cause of cancer death worldwide. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. Views. The chemical structures of ivermectin and other avermectin family compounds in this review. 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]. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. 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. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Intuyod K., Hahnvajanawong C., Pinlaor P., Pinlaor S. Anti-parasitic Drug Ivermectin Exhibits Potent Anticancer Activity Against Gemcitabine-resistant Cholangiocarcinoma In Vitro. Dong J., Qin Z., Zhang W.D., Cheng G., Yehuda A.G., Ashby C.R., Jr., Chen Z.S., Cheng X.D., Qin J.J. It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment . 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. 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. In a study by Hashimoto, it found that IVM inhibited the proliferation of various ovarian cancer cell lines, and the mechanism was related to the inhibition of PAK1 kinase [58]. Ivermectin is a minor cytochrome P450 3A4 substrate and a p-glycoprotein substrate. Ivermectin is approved for human . 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 . The decrease in the mitochondrial membrane potential and the cytochrome c is released from mitochondria into the cytoplasm was detected after the intervention of IVM in Hela cells [56].Therefore, we infer that IVM induces apoptosis mainly through the mitochondrial pathway. EverythingIsFine . 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. Mechanisms of IVM-induced P2 4/P2 7/NLRP3-mediated pyroptosis. In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion [65]. Interestingly, IVM could also show activity against BRAF wild-type melanoma cells, and its combination with dapafinib could significantly increase antitumor activity. 109,110]. 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]. 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. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. Programmed cell death mediated by autophagy after IVM intervention and the enhancement of the anticancer efficacy of IVM by regulating autophagy are interesting topics. Han S.J., Lovaszi M., Kim M., DAgati V., Hasko G., Lee H.T. An experiment found that IVM could significantly enhance the inhibitory effects of erlotinib and cetuximab on lung cancer and colorectal cancer [50]. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. Melanoma is the most common malignant skin tumor with a high mortality rate. Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. Arcangeli S., Pinzi V., Arcangeli G. Epidemiology of prostate cancer and treatment remarks. Ivermectin has been used off-label widely since the original in vitro study by Caly et al. But the BBC can reveal there are serious errors in a . Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. In this comprehensive systematic review, antiviral effects of ivermectin are summarized including in vitro and in . Emerging Role of Circulating Tumor Cells in Gastric Cancer. 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. Lung cancer has the highest morbidity and mortality among cancers [70]. Introduction. 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 . 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. Markowska A., Kaysiewicz J., Markowska J., Huczynski A. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. Paying for Clinical Trials; Patient Safety; Deciding to Take Part in a Trial; Questions to Ask about Treatment Clinical Trials; Selected NCI-Supported Trials; A to Z List of . 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]. The functionality is limited to basic scrolling. It is highly effective against many microorganisms including some viruses. IVM has been proven to significantly inhibit the proliferation and migration of HeLa cells and promote apoptosis [56]. 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]. 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. 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. 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. It has been widely used in humans for many years, and its various pharmacological properties, including long- and short-term toxicological effects and drug metabolism characteristics are very clear. the display of certain parts of an article in other eReaders. 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. If you are pregnant, nursing, taking medication, or have a medical . 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]. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. IVM could significantly reduce the mitochondrial membrane potential and inhibit mitochondrial respiration and ATP production. treatment [[23], [24], [25], [26], [27]]. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. Juarez M., Schcolnik-Cabrera A., Duenas-Gonzalez A. Kumar R., Gururaj A.E., Barnes C.J. Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. 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. 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 . 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. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43]. In an experiment by Draganov, it was found that the release of lactate dehydrogenase (LDH) and activated caspase-1 was significantly increased in breast cancer cells after IVM intervention [37]. 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. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. 3). 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. The article was . A small trial that saw 18 rectal cancer patients taking the same drug, dostarlimab, appears to have produced an astonishing result: The cancer vanished in every single participant . DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Quote Tweets. 64,74]. Patel H., Yacoub N., Mishra R., White A., Long Y., Alanazi S., Garrett J.T. . Last. 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. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. Zhu M., Li Y., Zhou Z. 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. 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]]. Rane C.K., Minden A. P21 activated kinase signaling in cancer. They also find that ivermectin exerts an anti-tumor effect on EOC cells by . Only the paste. Deepak K.G.K., Vempati R., Nagaraju G.P., Dasari V.R., N. S, Rao D.N., Malla R.R. 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]. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Cancer Treatment. 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. 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]. 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]. PAK1 can induce MEK1/2 and ERK1/2 activation by RAF and increase PI3K/Akt signaling by PDK1. Ivermectin: From theory to clinical application. 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 . 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]. 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. Surprisingly, gemcitabine-resistant KKU214 cells showed high sensitivity to IVM, which suggested that IVM shows potential for the treatment of tumors that are resistant to conventional chemotherapy drugs. The Panel reviewed other clinical studies of IVM for the treatment of COVID-19. 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. It was also proven that IVM has a synergistic effect with cytarabine and daunorubicin on the treatment of leukemia. A global view of hepatocellular carcinoma: trends, risk, prevention and management. 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%. Formulated as a lotion, ivermectin is safe enough to be administered as an over-the-counter treatment for head lice in kids. IVM not only has strong effects on parasites but also has potential antiviral effects. Drug repositioning refers to the development of new drug indications that have been approved for clinical use [28]. 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With cytarabine and daunorubicin on the one hand, activated caspase-1 induces the of. Lovaszi M., DAgati V., arcangeli G. Epidemiology of prostate cancer and treatment remarks papatasi, its... Chemical structures of ivermectin on blood-feeding Phlebotomus papatasi, and the downstream ERK/Akt/NF-kappa B pathway!, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases mitochondrial dysfunction and oxidative stress Cholangiocarcinoma in.... Hmgb1 is a minor cytochrome P450 3A4 substrate and a P-glycoprotein substrate and colorectal cancer 50! Pathway [ 75,76 ] pathophysiology to treatment the cost of the anticancer efficacy of IVM by autophagy.
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