IVM could inhibit the DDX23/miR-12 signaling pathway by affecting the activity of DDX23 helicase, thereby inhibiting malignant biological behaviors. Therefore, this review summarized the latest findings on the anticancer effect of IVM and discussed the mechanism of the inhibition of tumor proliferation and the way that IVM induces tumor programmed cell death to provide a theoretical basis for the use of IVM as a potential anticancer drug. 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. Pyroptosis is a type of inflammatory cell death induced by inflammasomes. 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 . However, in special circumstances, autophagy may also help to induce apoptosis or necrosis [83]. Hashimoto H., Messerli S.M., Sudo T., Maruta H. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. 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. In addition, PAK1 facilitates Wnt/-catenin signaling, make -catenin accumulate in the cytoplasm and translocate to the nucleus. Nasopharyngeal carcinoma is a malignant tumor derived from epithelial cells of the nasopharyngeal mucosa. Two studied the effects of intensive physical treatment plus selenium or placebo in preventing AIE's, and two studied the effects of Ivermectin, Diethylcarbamazine (DEC) (anti-filarial agents) and penicillin as prophylactic treatment for adeno lymphangitis(ADL) versus placebo.Both selenium trials reported no inflammatory episodes during the . Guadalupe evaluated the effect of IVM on CSCs in the breast cancer cell line MDA-MB-231 [95]. Yan S., Ci X., Chen N., Chen C., Li X., Chu X., Li J., Deng X. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Therefore, combination therapy is the most common method of chemotherapy. It . 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. In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. 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. Moreover, the expression of the homeobox protein NANOG, octamer-binding protein 4 (OCT-4) and SRY-box 2 (SOX-2), which are closely related to the self-renewal and differentiation ability of stem cells in CSCs, were also significantly inhibited by IVM. Cervical cancer is one of the most common gynecological malignancies, resulting in approximately 530,000 new cases and 270,000 deaths worldwide each year. Approximately 80% of cases of liver cancer are caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection [42]. 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. The four faces of autophagy: implications for cancer therapy. 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]. 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. The authors speculated that IVM may mediate the occurrence of pyroptosis via the P2 4/P2 7/NLRP3 pathway (Fig. 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]. Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. Autophagy is a lysosomal-dependent form of programmed cell death. Several studies showed that the ivermectin has antitumor effects on a variety of cancer cells. Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. This was related to the induction of mitochondrial dysfunction and oxidative stress. Gong T., Liu L., Jiang W., Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. 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. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. RT @AFLDSorg: 'Ivermectin has anti-cancer properties.' @drCParks1 explains what the scientific research shows. The 5-year survival rate after diagnosis is approximately 47% [27,57]. Pouliot J.F., LHeureux F., Liu Z., Prichard R.K., Georges E. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Laing R., Gillan V., Devaney E. Ivermectin - Old Drug, New Tricks? Inflammasomes initiate the conversion of pro-caspase-1 via self-shearing into activated caspase-1. Intuyod K., Hahnvajanawong C., Pinlaor P., Pinlaor S. Anti-parasitic Drug Ivermectin Exhibits Potent Anticancer Activity Against Gemcitabine-resistant Cholangiocarcinoma In Vitro. Therefore, IVM should be used in combination with other drugs to achieve the best effect, while the specific medication plan used to combine IVM with other drugs remains to be explored. However, whether ivermectin affects CRC is still unclear. These participants received packages at their residences that contained either a dose of ivermectin or a placebo. In the past year, more than one million patients with gastric cancer have been diagnosed worldwide [38]. 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]. Based on the studies suggesting efficacy in prophylaxis combined with the known safety profile of ivermectin, a citywide prevention program using ivermectin for COVID-19 was implemented in Itaja, a southern . Deepak K.G.K., Vempati R., Nagaraju G.P., Dasari V.R., N. S, Rao D.N., Malla R.R. The majority of cervical cancers are caused by human papillomavirus (HPV) infection [54,55]. Nagata S. Apoptosis and Clearance of Apoptotic Cells. Ivermectin, an antiparasitic drug, has been shown to possess anti-inflammation, anti-virus, and antitumor properties. Gastric cancer is one of the most common malignant tumors worldwide. 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]. WASHINGTON Ivermectin, a controversial drug used commonly as a horse dewormer as well as a treatment for parasitic infections in humans, could be capable of treating COVID-19 patients and potentially ending the pandemic, some scientists claim.The team of researchers, including three U.S. government senior scientists, are calling for governments around the world to start treating . DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Background Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. This group explores and celebrates the successes of the repurposed drug Fenbendazole to help with cancer treatment. 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. In humans, the FDA has approved ivermectin to treat infections caused by some parasitic worms and, topically, for head lice and the skin disorder rosacea. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. 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. Furthermore, ivermectin was approved for the treatment of scabies by the World Health Organization based only on 10 randomized controlled trials, including 852 patients. Ivermectin induces apoptosis and autophagy is mutually regulated. The phenomenon of IVM-induced autophagy has also been reported in glioma and melanoma [ describing ivermectin activity against SARS-CoV-2, 22 and in Brazil, in particular, the use of ivermectin . We formerly reported that the combination of dichloroacetate, omeprazole, and tamoxifen blocked cancer progression by reducing lactic acid production and inducing superoxide production. 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. Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug. Elsevier Public Health Emergency Collection, HelaColorectal cancer (CC14, CC36, DLD1,Ls174 T)Ovarian cancer (SKOV3, OVCAR3, CAOV3)Renal cell carcinoma (SW-839, Caki-2, 786-O, A498, ACHN)Leukemia(K562, primary CD34, Glioma (U251, C6)Breast cancer(MCF-7, MDA-MB-231)Melanoma (SK-MEL-28), Breast cancer, Ovarian cancer, Nasopharyngeal carcinoma, Melanoma, Prostate cancer, Lung cancer Colorectal cancer. Rane C.K., Minden A. P21 activated kinase signaling in cancer. Methods We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 . Rectal cancer. 1 On the other hand, caspase-1 activated by GSDMD triggers pyroptosis independent of apoptosis. Yang J.D., Hainaut P., Gores G.J., Amadou A., Plymoth A., Roberts L.R. 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.". Liu J., Liang H., Chen C., Wang X., Qu F., Wang H., Yang K., Wang Q., Zhao N., Meng J., Gao A. Ivermectin induces autophagy-mediated cell death through the AKT/mTOR signaling pathway in glioma cells. However, whether ivermectin affects CRC is still unclear. 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. It is characterized by double-layered or multilayered vacuolar structures containing cytoplasmic components, which are known as autophagosomes [77]. Deng F., Xu Q., Long J., Xie H. Suppressing ROSTFE3dependent autophagy enhances ivermectininduced apoptosis in human melanoma cells. 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. Effects of ivermectin on blood-feeding Phlebotomus papatasi, and the promastigote stage of Leishmania major. We use cookies to enhance your experience. 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. aAnhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui Province 233030, China, bClinical Medical Department, Bengbu Medical College, Bengbu, Anhui Province 233030, China, cDepartment of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui Province 233030, China, dDepartment of Microbiology and Parasitology, Bengbu Medical College, Bengbu, Anhui Province 233030, China, eSchool of Fundamental Sciences, Bengbu Medical College, Bengbu, Anhui Province 233030, China. In research to screen potential targets for the treatment of ovarian cancer through the use of an shRNA library and a CRISPR/Cas9 library, the oncogene KPNB1 was detected. You may notice problems with However, in breast cancer cell experiments, it was also found that IVM could induce autophagy, and enhanced autophagy could increase the anticancer activity of IVM [37]. 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. A study published in the peer-reviewed American Journal of Therapeutics showed that the cost of ivermectin for other treatments in Bangladesh is around $0.60 to $1.80 for a five-day course. PRR can identify pathogen-associated molecular patterns (PAMPs) that are structurally stable and evolutionarily conserved on the surface of pathogenic microorganisms and damage-associated molecular patterns (DAMPs) produced by damaged cells [84,85]. 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]. Experiments showed that IVM inhibited the proliferation of human glioblastoma U87 and T98 G cells in a dose-dependent manner and induced apoptosis in a caspase-dependent manner [63]. 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. It included data from Surgisphere, a company that also provided inaccurate patient data . 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. This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [[101], [102], [103]]. 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. Interestingly, IVM and paclitaxel have a synergistic effect on ovarian cancer, and combined treatment in in vivo experiments almost completely inhibited tumor growth. Ivermectin is approved for human . 4), but there is no specific evidence to prove this speculation. 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]. In another study, IVM inhibited the proliferation of U251 and C6 glioma cells by inhibiting the Akt/mTOR pathway [64]. 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 . IVM has also shown beneficial effects against other parasitic diseases, such as malaria [11,12], trypanosomiasis [13], schistosomiasis [14], trichinosis [15] and leishmaniasis [16]. EverythingIsFine . Therefore, in future research, it is necessary to continue to explore the specific mechanism of IVM involved in regulating the tumor microenvironment, angiogenesis and EMT. 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. RAS activation directly initiates PAK1, MAPK and PI3K/Akt pathway. 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. PAK1 is at the junction of these pathways. Genetic and molecular epidemiology of adult diffuse glioma. 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). 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