Emerging Role of Circulating Tumor Cells in Gastric Cancer. 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. 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. The discoverers of IVM, Japanese scientist Satoshi mura and Irish scientist William C. Campbell, won the Nobel Prize in Physiology or Medicine in 2015 [7,8]. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of twodimensional similarity . Draganov D., Gopalakrishna-Pillai S., Chen Y.R., Zuckerman N., Moeller S., Wang C., Ann D., Lee P.P. 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]. 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). Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin. IVM can promote ROS release in cancer cells by P2 4/P2 7 receptors. 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]. Previous studies have indicated that PAK1 is located at the intersection of multiple signaling pathways related to tumorigenesis and is a key regulator of cancer signaling networks (Fig. Mechanisms of IVM-induced P2 4/P2 7/NLRP3-mediated pyroptosis. Last Updated on January 5, 2023 by Shaun Snapp. Overall, IVM can induce autophagy through PAK1/Akt/mTOR pathway to represses the growth of cancer cells independent of apoptosis. Wang J., Seebacher N., Shi H., Kan Q., Duan Z. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Ivermectin induces apoptosis and autophagy is mutually regulated. 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. 672. Markowska A., Kaysiewicz J., Markowska J., Huczynski A. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. Gastric cancer is one of the most common malignant tumors worldwide. Avermectin family drugs such as selamectin [36,41,113], and doramectin [114] also have anticancer effects, as previously reported. Nambaras study showed that IVM could significantly inhibit the proliferation of gastric cancer cells in vivo and in vitro and that the inhibitory effect of IVM depended on the expression of Yes-associated protein 1(YAP1)[39]. Ivermectin: From theory to clinical application. In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion [65]. Existing research is sufficient to demonstrate the great potential of IVM and its prospects as a novel promising anticancer drug after additional research. IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. Programmed cell death mediated by autophagy after IVM intervention and the enhancement of the anticancer efficacy of IVM by regulating autophagy are interesting topics. Biochemical and Biophysical Research Communications. MDR of tumor cells is the main cause of relapses and deaths after chemotherapy [97]. 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. A Colombian health worker . 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. 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 . The majority of cervical cancers are caused by human papillomavirus (HPV) infection [54,55]. The objective of this study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116. By Laurie McGinley. 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. Furthermore, ivermectin was approved for the treatment of scabies by the World Health Organization based only on 10 randomized controlled trials, including 852 patients. Background: Ivermectin has demonstrated different mechanisms of action that potentially protect from both coronavirus disease 2019 (COVID-19) infection and COVID-19-related comorbidities. 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. the display of certain parts of an article in other eReaders. . 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. (Ub:Ubiquitination, P:Phosphorylation). 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]. It included data from Surgisphere, a company that also provided inaccurate patient data . Kane N.S., Hirschberg B., Qian S., Hunt D., Thomas B., Brochu R., Ludmerer S.W., Zheng Y., Smith M., Arena J.P., Cohen C.J., Schmatz D., Warmke J., Cully D.F. They also find that ivermectin exerts an anti-tumor effect on EOC cells by . April 8, 2021 at 8:00 a.m. EDT. As the cost of the research and development of new anticancer drugs continues to increase, drug repositioning has become increasingly important. In a study that screened Wnt pathway inhibitors, IVM inhibited the proliferation of multiple cancers, including the colorectal cancer cell lines CC14, CC36, DLD1, and Ls174 T, and promoted apoptosis by blocking the Wnt pathway [41]. Mingyang Tang, Xiaodong Hu, [], and Qiang Fang. Epigenetic therapy for ovarian cancer: promise and progress. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. In addition, IVM regulated the expression of the epithelial mesenchymal-transition (EMT) related gene E-cadherin to restore the sensitivity of TNBC cells to tamoxifen, which implies the possibility that IVM functions as an epigenetic regulator in the treatment of cancer[36]. Last. It is highly effective against many microorganisms including some viruses. Intuyod's experiment found that IVM inhibited the proliferation of KKU214 cholangiocarcinoma cells in a dose- and time-dependent manner [44]. HMGB1 is a chromatin protein present in all cells and its . Diao H., Cheng N., Zhao Y., Xu H., Dong H., Thamm D.H., Zhang D., Lin D. Ivermectin inhibits canine mammary tumor growth by regulating cell cycle progression and WNT signaling. The FDA first issued a warning in April 2020 that ivermectin intended for use in animals should not be used to treat COVID-19 . P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. 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. However, NAC reversed the effect of IVM, which indicated that IVM increased TFE3-dependent autophagy through the ROS signaling pathway. Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. Degterev A., Yuan J. Ivermectin is generally given with water on an empty stomach; however, administering ivermectin with food increases its bioavailability. 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. In mid-2020, an ivermectin study published in the prestigious New England Journal of Medicine was retracted. 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. Therefore, CSCs have been widely recognized as the main cause of recurrence after treatment [93,94]. Cancer stem cells and self-renewal. It is impossible to prove a negative, so the TOGETHER trial cannot prove that ivermectin is not useful in treating COVID. Rane C.K., Minden A. P21 activated kinase signaling in cancer. 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. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. 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 . 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. 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). We are experimenting with display styles that make it easier to read articles in PMC. 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 . Lung cancer has the highest morbidity and mortality among cancers [70]. RAS activation directly initiates PAK1, MAPK and PI3K/Akt pathway. 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 . Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment. When the external environment is suitable, CSCs will rapidly proliferate to reactivate the formation and growth of tumors. The inflammasome is a multimolecular complex containing pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. 15 Jan 2023 21:28:26 Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial Lim SCL, Hor CP, Tay KH, et al. 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. PAK1 cross regulate multiple signal pathways. Executive Summary. Diehn M., Clarke M.F. Genetic and molecular epidemiology of adult diffuse glioma. You may notice problems with 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. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. natem | @natem | 1 day ago. McKerrow J.H. 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. 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. A recent double-blind randomized study in Cali, Colombia found that ivermectin, used among adults with mild cases of COVID-19, "did not significantly improve the time to resolution of symptoms . Recently, ivermectin, a well-known anti-parasite drug, was reported to share the same mechanisms with them and have anti-tumor activity. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. Ivermectin neither reduced hospital admissions for worsening COVID-19 nor shortened the time that infected patients spent in the emergency room, according to data from a large randomized . 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. But ivermectin is not a miracle cure for COVID-19, and there's no . Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. 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. Views. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. treatment [[23], [24], [25], [26], [27]]. 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. Cancer cells exposure to IVM can be induced to generate ROS generation and reduce membrane potential of mitochondria. already built in. 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 . This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells [52]. Katz N., Araujo N., Coelho P.M.Z., Morel C.M., Linde-Arias A.R., Yamada T., Horimatsu Y., Suzuki K., Sunazuka T., Omura S. Ivermectin efficacy against Biomphalaria, intermediate host snail vectors of Schistosomiasis. Among cancers [ 70 ] in treating COVID ivermectin intended for use in animals not! This study was to evaluate the influence of ivermectin on CRC using CRC cell lines SW480 and SW1116 study in. 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