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. Draganov D., Gopalakrishna-Pillai S., Chen Y.R., Zuckerman N., Moeller S., Wang C., Ann D., Lee P.P. As mentioned above, the broad-spectrum antiparasitic drug IVM, which is widely used in the field of parasitic control, has many advantages that suggest that it is worth developing as a potential new anticancer drug. 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. Drug repositioning refers to the development of new drug indications that have been approved for clinical use [28]. 108K. 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]. Geyer J., Gavrilova O., Petzinger E. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice. The ACTIV-6 study enrolled 1,800 participants. Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin. It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. Dammann K., Khare V., Gasche C. Tracing PAKs from GI inflammation to cancer. Deepak K.G.K., Vempati R., Nagaraju G.P., Dasari V.R., N. S, Rao D.N., Malla R.R. 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 CID6321424), avermectin(PubChem CID6434889), selamectin(PubChem CID9578507), doramectin(PubChem CID9832750), moxidectin(PubChem CID9832912). Importantly, IVM is an established drug used for the treatment of parasitic diseases such as river blindness and elephantiasis. Udensi U.K., Fagbenro-Beyioku A.F. 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. Cancer cells exposure to IVM can be induced to generate ROS generation and reduce membrane potential of mitochondria. Ivermectin is generally given with water on an empty stomach; however, administering ivermectin with food increases its bioavailability. Introduction. . 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. 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. Rectal cancer. Dominguez-Gomez G., Chavez-Blanco A., Medina-Franco J.L., Saldivar-Gonzalez F., Flores-Torrontegui Y., Juarez M., Diaz-Chavez J., Gonzalez-Fierro A., Duenas-Gonzalez A. Ivermectin as an inhibitor of cancer stemlike cells. Ivermectin-induced cytostatic autophagy also leads to suppression of tumor growth in breast cancer xenografts, causing researchers to believe there is scope for using ivermectin to inhibit breast . Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. Ivermectin induces apoptosis and autophagy is mutually regulated. The authors report no declarations of interest. "It is a far cry from an in vitro lab replication to helping humans," said Dr. Nasia Safdar, medical director of infection prevention at the University of Wisconsin-Madison Hospital. 2 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. 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. Wang J., Xu Y., Wan H., Hu J. Quote Tweets. Prichard R.K., Geary T.G. Subsequently, the inactivation Akt/mTOR signaling cannot inhibit the formation of the Beclin-1 complex, thus inducing the formation autophagosome. Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. It was based on a very small flawed 2002 study mentioned in a 2011 study. IVM can promote ROS release in cancer cells by P2 4/P2 7 receptors. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. 64,74]. ATP binding transport family-mediated drug efflux and overexpression of P-glycoprotein (P-gp) are widely considered to be the main causes of tumor MDR [[98], [99], [100]]. 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. 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. Only the paste. However, there is no systematic and clear conclusion regarding the related molecular mechanism. Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. ). Mingyang Tang, Xiaodong Hu, [], and Qiang Fang. 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. 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. PAK1 can also activate pro-inflammatory pathways by facilitating nuclear activation of NF-kappa B. Kobayashi Y., Banno K., Kunitomi H., Tominaga E., Aoki D. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. Activated caspase-1 can cause pro-IL-1 and pro-IL-18 to mature and to be secreted. Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. 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 is characterized by double-layered or multilayered vacuolar structures containing cytoplasmic components, which are known as autophagosomes [77]. The study was done by . Gao A., Wang X., Xiang W., Liang H., Gao J., Yan Y. IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. Colorectal cancer (CRC) is the third most common cancer worldwide and still lacks effective therapy. Autophagy-Independent Functions of the Autophagy Machinery. EOC is the fifth leading cause of cancer-related deaths in women and has a particularly grim outlook upon diagnosis. Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. 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 . Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., Dewhirst M.W., Bigner D.D., Rich J.N. 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. describing ivermectin activity against SARS-CoV-2, 22 and in Brazil, in particular, the use of ivermectin . 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 . Ivermectin is used to treat river blindness (onchocerciasis), intestinal infection from threadworms (strongyloidiasis), and other kinds of worm infections. 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. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. 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. We use cookies to enhance your experience. Guadalupe evaluated the effect of IVM on CSCs in the breast cancer cell line MDA-MB-231 [95]. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [[101], [102], [103]]. 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. Moreover, IVM was also found to have a good inhibitory effect on the prostate cancer cell line DU145 [51]. 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 Ivermectin can turn "cold" breast tumors "hot" We studied the effects of ivermectin in vivo using the 4T1 mouse model of TNBC. In a study that screened drugs for the treatment of nasopharyngeal cancer, IVM significantly inhibited the development of nasopharyngeal carcinoma in nude mice at doses that were not toxic to normal thymocytes [69]. 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]. In mid-2020, an ivermectin study published in the prestigious New England Journal of Medicine was retracted. It is impossible to prove a negative, so the TOGETHER trial cannot prove that ivermectin is not useful in treating COVID. We believe that deeper exploration of the mechanism can further guide the use of IVM in the treatment of cancer. Old wine in new bottles: Drug repurposing in oncology. 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. 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. Ivermectin has been called a Covid "miracle" drug, championed by vaccine opponents, and recommended by health authorities in some countries. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update. The DDX23 helicase activity affects the expression of miR-12 [66]. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. These results indicated the significance of applying IVM for the treatment of chemotherapy patients with MDR. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. 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. You may switch to Article in classic view. 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. On Aug. 23, a judge issued an emergency order to the hospital to begin administering 30 milligrams of ivermectin a day to the patient, as prescribed by a Front Line COVID-19 Critical Care Alliance . , Ann D., Lee P.P a fatal malignant tumor produced by gene mutation in breast cells! Induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress of mitochondria study mentioned in 2011! Have also found that IVM could promote the death of tumor cells by 4/P2... Evaluated the effect of IVM on CSCs in the treatment of cancer apoptosis in chronic myeloid leukemia through inducing dysfunction... 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