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      Ivermectin, a potential anticancer drug derived from an antiparasitic drug

      review-article
      a , b , 1 , c , 1 , a , d , a , d , a , b , a , b , a , b , a , d , a , d , e , *
      Pharmacological Research
      Elsevier Ltd.
      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, cancer, drug repositioning

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          Graphical abstract

          Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Ivermectin induces apoptosis and autophagy is mutually regulated. 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.

          Highlights

          • Ivermectin effectively suppresses the proliferation and metastasis of cancer cells and promotes cancer cell death at doses that are nontoxic to normal cells.

          • Ivermectin shows excellent efficacy against conventional chemotherapy drug-resistant cancer cells and reverses multidrug resistance.

          • Ivermectin combined with other chemotherapy drugs or targeted drugs has powerful effects on cancer.

          • The structure of crosstalk centered on PAK1 kinase reveals the mechanism by which ivermectin regulates multiple signaling pathways.

          • Ivermectin has been used to treat parasitic diseases in humans for many years and can quickly enter clinical trials for the treatment of tumors.

          Abstract

          Ivermectin is a macrolide antiparasitic drug with a 16-membered ring that is widely used for the treatment of many parasitic diseases such as river blindness, elephantiasis and scabies. Satoshi ōmura and William C. Campbell won the 2015 Nobel Prize in Physiology or Medicine for the discovery of the excellent efficacy of ivermectin against parasitic diseases. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. This suggests that ivermectin may be an anticancer drug with great potential. Here, we reviewed the related mechanisms by which ivermectin inhibited the development of different cancers and promoted programmed cell death and discussed the prospects for the clinical application of ivermectin as an anticancer drug for neoplasm therapy.

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          Most cited references115

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          Cancer statistics, 2019

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.
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            A global view of hepatocellular carcinoma: trends, risk, prevention and management

            Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Risk factors for HCC include chronic hepatitis B and hepatitis C, alcohol addiction, metabolic liver disease (particularly nonalcoholic fatty liver disease) and exposure to dietary toxins such as aflatoxins and aristolochic acid. All these risk factors are potentially preventable, highlighting the considerable potential of risk prevention for decreasing the global burden of HCC. HCC surveillance and early detection increase the chance of potentially curative treatment; however, HCC surveillance is substantially underutilized, even in countries with sufficient medical resources. Early-stage HCC can be treated curatively by local ablation, surgical resection or liver transplantation. Treatment selection depends on tumour characteristics, the severity of underlying liver dysfunction, age, other medical comorbidities, and available medical resources and local expertise. Catheter-based locoregional treatment is used in patients with intermediate-stage cancer. Kinase and immune checkpoint inhibitors have been shown to be effective treatment options in patients with advanced-stage HCC. Together, rational deployment of prevention, attainment of global goals for viral hepatitis eradication, and improvements in HCC surveillance and therapy hold promise for achieving a substantial reduction in the worldwide HCC burden within the next few decades.
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              The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro

              Although several clinical trials are now underway to test possible therapies, the worldwide response to the COVID-19 outbreak has been largely limited to monitoring/containment. We report here that Ivermectin, an FDA-approved anti-parasitic previously shown to have broad-spectrum anti-viral activity in vitro, is an inhibitor of the causative virus (SARS-CoV-2), with a single addition to Vero-hSLAM cells 2 hours post infection with SARS-CoV-2 able to effect ∼5000-fold reduction in viral RNA at 48 h. Ivermectin therefore warrants further investigation for possible benefits in humans.
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                Author and article information

                Journal
                Pharmacol Res
                Pharmacol. Res
                Pharmacological Research
                Elsevier Ltd.
                1043-6618
                1096-1186
                21 September 2020
                21 September 2020
                Affiliations
                [a ]Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui Province 233030, China
                [b ]Clinical Medical Department, Bengbu Medical College, Bengbu, Anhui Province 233030, China
                [c ]Department of Histology and Embryology, Bengbu Medical College, Bengbu, Anhui Province 233030, China
                [d ]Department of Microbiology and Parasitology, Bengbu Medical College, Bengbu, Anhui Province 233030, China
                [e ]School of Fundamental Sciences, Bengbu Medical College, Bengbu, Anhui Province 233030, China
                Author notes
                [* ]Corresponding author at: Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui Province 233030, China.
                [1]

                These authors contributed equally.

                Article
                S1043-6618(20)31515-2 105207
                10.1016/j.phrs.2020.105207
                7505114
                a7475b37-9d61-45c5-bcaa-cbb2e997d1e7
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. 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. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                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,cancer,drug repositioning

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