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]. EverythingIsFine . 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. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. The secondary objectives of the study include evaluating the following efficacy outcomes: objective response rate (ORR), progression free survival (PFS), overall survival (OS), duration of response (DOR . In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [[2], [3], [4], [5]] (Fig. 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. On the one hand, autophagy can help tumors adapt to the nutritional deficiency of the tumor microenvironment, and to a certain extent, protect tumor cells from chemotherapy- or radiotherapy- induced injury. 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. IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. 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. 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. Siegel R.L., Miller K.D., Jemal A. We have already mentioned that IVM plays an anticancer role in various tumors by regulating pathways closely related to cancer development. However, to date, no exact target for IVM action has been found. This suggests that ivermectin may be an anticancer drug with great potential. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. 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. Experiments confirmed that IVM could significantly inhibit the proliferation of five renal cell carcinoma cell lines without affecting the proliferation of normal kidney cells, and its mechanism may be related to the induction of mitochondrial dysfunction [48]. 36. 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]. 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]]. Our scientists pursue every aspect of cancer researchfrom exploring the biology of genes and cells, to developing immune-based treatments, uncovering the causes of metastasis, and more. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. 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. A clinical trial of 476 patients found ivermectin didn't improve the recovery time in patients who had COVID-19. Glioblastoma is the deadliest glioma, with a median survival time of only 14-17 months [61,62]. Tracey Savich, owner of Rolling Hills General Store, felt the need to warn customers against using veterinary . It is characterized by double-layered or multilayered vacuolar structures containing cytoplasmic components, which are known as autophagosomes [77]. Second, IVM seems to induce mixed cell death in tumor cells, which is also a controversial issue. We found that the anticancer . Malignant tumors are one of the most serious diseases that threaten human health and social development today, and chemotherapy is one of the most important methods for the treatment of malignant tumors. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Its morbidity has increased by an average of 2% annually worldwide and the clinical treatment effect is not satisfactory [[45], [46], [47]]. Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Ivermectin induces apoptosis and autophagy is mutually regulated. A study published in this week's Journal of the American Medical Association ( JAMA) reported on a double-blind placebo controlled randomized trial of nearly 1600 adults with mild to moderate . These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment. Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. What this study does and does not show. 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. In a study that . Doramectin--a potent novel endectocide. Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. The study was done by . 15 Jan 2023 21:28:26 The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. In addition, characteristic pyroptosis phenomena such as cell swelling and rupturing were observed. "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. Abstract. Ivermectin is proven to treat a variety of different cancers. Cancer stem cells and self-renewal. Following the study, the FDA released a letter out of concern warning consumers not to self-medicate with ivermectin products intended for animals. We found that IVM inhibits tumor cell development in a PAK1-dependent manner in most cancers. The study group included adult patients from 12 cities throughout Brazil, where ivermectin has been widely embraced and utilized since the early months of the pandemic. 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. Wang's experiment found that IVM could selectively induce mitochondrial dysfunction and oxidative stress, causing chronic myeloid leukemia K562 cells to undergo increased caspase-dependent apoptosis compared with normal bone marrow cells [53]. 108K. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of twodimensional similarity . Kumar R., Gururaj A.E., Barnes C.J. You may notice problems with Subsequently, NLRP3 Inflammasome initiates pro-caspase-1 to self-shear into mature caspase-1. An experiment found that IVM could significantly enhance the inhibitory effects of erlotinib and cetuximab on lung cancer and colorectal cancer [50]. Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. As reported earlier, it may have anti-tumor, anti metastasis properties against some cancers. Li X., Lewis M.T., Huang J., Gutierrez C., Osborne C.K., Wu M.F., Hilsenbeck S.G., Pavlick A., Zhang X., Chamness G.C., Wong H., Rosen J., Chang J.C. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Arcangeli S., Pinzi V., Arcangeli G. Epidemiology of prostate cancer and treatment remarks. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. 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 . The relationship between apoptosis and autophagy is very complicated, and the cross talk between the two plays a vital role in the development of cancer [82]. 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. In addition, researchers also used the Akt activator CA-Akt to prove that IVM mainly induces autophagy by inhibiting the phosphorylation of Akt and mTOR (Fig. Most of the anticancer research performed on the avermectin family has been focused on avermectin and IVM until now. 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 . 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]. IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. the display of certain parts of an article in other eReaders. This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. Mechanisms of IVM-induced P2 4/P2 7/NLRP3-mediated pyroptosis. Received 2020 Jun 5; Revised 2020 Sep 11; Accepted 2020 Sep 11. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. Mechanisms of IVM-induced mitochondria-mediated apoptosis. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells [52]. A drug screening study of TNBC showed that IVM could be used as a SIN3-interaction domain (SID) mimic to selectively block the interaction between SID and paired a-helix2. It has a good effect on the treatment of parasitic diseases such as river blindness, elephantiasis, and scabies. 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. PAK1 can induce MEK1/2 and ERK1/2 activation by RAF and increase PI3K/Akt signaling by PDK1. Patel H., Yacoub N., Mishra R., White A., Long Y., Alanazi S., Garrett J.T. Obviously, the existing results suggest that IVM-induced apoptosis and autophagy also exhibit cross talk. 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. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. All of the above findings indicate the potential of IVM as an autophagy activator to induce autophagy-dependent death in tumor cells. Moreover, IVM was also found to have a good inhibitory effect on the prostate cancer cell line DU145 [51]. Colorectal cancer (CRC) is the third most common cancer worldwide and still lacks effective therapy. 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]. Furthermore, ivermectin was approved for the treatment of scabies by the World Health Organization based only on 10 randomized controlled trials, including 852 patients. The chemical structures of ivermectin and other avermectin family compounds in this review. 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. In addition, IVM shows potential for clinical application in asthma [20] and neurological diseases [21]. Subsequently, the inactivation Akt/mTOR signaling cannot inhibit the formation of the Beclin-1 complex, thus inducing the formation autophagosome. 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. 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]. p21-activated kinases in cancer. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. By Laurie McGinley. ). Approximately 80% of cases of liver cancer are caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection [42]. describing ivermectin activity against SARS-CoV-2, 22 and in Brazil, in particular, the use of ivermectin . It is impossible to prove a negative, so the TOGETHER trial cannot prove that ivermectin is not useful in treating COVID. Pouliot J.F., LHeureux F., Liu Z., Prichard R.K., Georges E. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. But the result of . 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]. For example, it was found in SK-MEL-28 melanoma cells that IVM can promote apoptosis as well as autophagy [74]. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Interestingly, IVM could also show activity against BRAF wild-type melanoma cells, and its combination with dapafinib could significantly increase antitumor activity. The ePub format uses eBook readers, which have several "ease of reading" features DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. The present study represents the first study evaluating the anticancer efficacy of ivermectin in pancreatic cancer. 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. 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]. The incidence is obviously regional and familial, and Epstein-Barr virus (EBV) infection is closely related [68]. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. A study published in JAMA Network this month estimated private and Medicare plans may have paid nearly $2.5 million for ivermectin prescriptions in the week of Aug. 13 alone. 4), but there is no specific evidence to prove this speculation. Satoshi mura 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. 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 . Loibl S., Gianni L. HER2-positive breast cancer. 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 . 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]. 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]]. 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. Summary of IVM promotes programmed cell death. An early study using cells in petri dishes suggested that ivermectin has antiviral properties at very high concentrations and could inhibit the pandemic coronavirus, SARS-CoV-2. The functionality is limited to basic scrolling. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43]. Harbeck N., Penault-Llorca F., Cortes J., Gnant M., Houssami N., Poortmans P., Ruddy K., Tsang J., Cardoso F. Breast cancer. 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. 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. 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. OBrien C.A., Kreso A., Jamieson C.H. Zanconato F., Cordenonsi M., Piccolo S. YAP and TAZ: a signalling hub of the tumour microenvironment. Recently scientists have discovered that IVM has a strong anticancer effect. MDR of tumor cells is the main cause of relapses and deaths after chemotherapy [97]. Interestingly, IVM and paclitaxel have a synergistic effect on ovarian cancer, and combined treatment in in vivo experiments almost completely inhibited tumor growth. Abstract. Campbell W.C., Fisher M.H., Stapley E.O., Albers-Schonberg G., Jacob T.A. 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. The Prime Minister of Malaysia proclaimed a state of Emergency Ordinance on the 12th January 2021. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. 1-26 However, those studies have limitations that make them less definitive and informative than the studies summarized in the table. Nappi's experiment also proved that IVM combined with erlotinib to achieved a synergistic killing effect by regulating EGFR activity and in HCC827 lung cancer cells [50]. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. 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. This group explores and celebrates the successes of the repurposed drug Fenbendazole to help with cancer treatment. Melanoma is the most common malignant skin tumor with a high mortality rate. Galluzzi L., Green D.R. 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. Table 1, the main form of IVM induced programmed cell death is apoptosis. Kircik L.H., Del Rosso J.Q., Layton A.M., Schauber J. (1) Although a large number of research results indicate that IVM affects multiple signaling pathways in tumor cells and inhibits proliferation, IVM may cause antitumor activity in tumor cells through specific targets. Ravegnini G., Sammarini G., Nannini M., Pantaleo M.A., Biasco G., Hrelia P., Angelini S. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. Despite the large number of related studies, there are still some key issues that have not been resolved. I take small doses of 6-12 mg regularly (3-4 x/week) after reading about it at NIH.gov, which someone else has now posted. The combination of drugs can effectively increase efficacy, reduce toxicity or delay drug resistance. But the BBC can reveal there are serious errors in a . Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. 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 . Antoszczak M., Markowska A., Markowska J., Huczynski A. 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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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]. EverythingIsFine . 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. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. The secondary objectives of the study include evaluating the following efficacy outcomes: objective response rate (ORR), progression free survival (PFS), overall survival (OS), duration of response (DOR . In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [[2], [3], [4], [5]] (Fig. 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. On the one hand, autophagy can help tumors adapt to the nutritional deficiency of the tumor microenvironment, and to a certain extent, protect tumor cells from chemotherapy- or radiotherapy- induced injury. 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. IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. 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. 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. Siegel R.L., Miller K.D., Jemal A. We have already mentioned that IVM plays an anticancer role in various tumors by regulating pathways closely related to cancer development. However, to date, no exact target for IVM action has been found. This suggests that ivermectin may be an anticancer drug with great potential. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. 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. Experiments confirmed that IVM could significantly inhibit the proliferation of five renal cell carcinoma cell lines without affecting the proliferation of normal kidney cells, and its mechanism may be related to the induction of mitochondrial dysfunction [48]. 36. 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]. 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]]. Our scientists pursue every aspect of cancer researchfrom exploring the biology of genes and cells, to developing immune-based treatments, uncovering the causes of metastasis, and more. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. 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. A clinical trial of 476 patients found ivermectin didn't improve the recovery time in patients who had COVID-19. Glioblastoma is the deadliest glioma, with a median survival time of only 14-17 months [61,62]. Tracey Savich, owner of Rolling Hills General Store, felt the need to warn customers against using veterinary . It is characterized by double-layered or multilayered vacuolar structures containing cytoplasmic components, which are known as autophagosomes [77]. Second, IVM seems to induce mixed cell death in tumor cells, which is also a controversial issue. We found that the anticancer . Malignant tumors are one of the most serious diseases that threaten human health and social development today, and chemotherapy is one of the most important methods for the treatment of malignant tumors. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Its morbidity has increased by an average of 2% annually worldwide and the clinical treatment effect is not satisfactory [[45], [46], [47]]. Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Ivermectin induces apoptosis and autophagy is mutually regulated. A study published in this week's Journal of the American Medical Association ( JAMA) reported on a double-blind placebo controlled randomized trial of nearly 1600 adults with mild to moderate . These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment. Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. What this study does and does not show. 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. In a study that . Doramectin--a potent novel endectocide. Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. The study was done by . 15 Jan 2023 21:28:26 The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. In addition, characteristic pyroptosis phenomena such as cell swelling and rupturing were observed. "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. Abstract. Ivermectin is proven to treat a variety of different cancers. Cancer stem cells and self-renewal. Following the study, the FDA released a letter out of concern warning consumers not to self-medicate with ivermectin products intended for animals. We found that IVM inhibits tumor cell development in a PAK1-dependent manner in most cancers. The study group included adult patients from 12 cities throughout Brazil, where ivermectin has been widely embraced and utilized since the early months of the pandemic. 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. Wang's experiment found that IVM could selectively induce mitochondrial dysfunction and oxidative stress, causing chronic myeloid leukemia K562 cells to undergo increased caspase-dependent apoptosis compared with normal bone marrow cells [53]. 108K. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of twodimensional similarity . Kumar R., Gururaj A.E., Barnes C.J. You may notice problems with Subsequently, NLRP3 Inflammasome initiates pro-caspase-1 to self-shear into mature caspase-1. An experiment found that IVM could significantly enhance the inhibitory effects of erlotinib and cetuximab on lung cancer and colorectal cancer [50]. Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. As reported earlier, it may have anti-tumor, anti metastasis properties against some cancers. Li X., Lewis M.T., Huang J., Gutierrez C., Osborne C.K., Wu M.F., Hilsenbeck S.G., Pavlick A., Zhang X., Chamness G.C., Wong H., Rosen J., Chang J.C. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Arcangeli S., Pinzi V., Arcangeli G. Epidemiology of prostate cancer and treatment remarks. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. 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 . The relationship between apoptosis and autophagy is very complicated, and the cross talk between the two plays a vital role in the development of cancer [82]. 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. In addition, researchers also used the Akt activator CA-Akt to prove that IVM mainly induces autophagy by inhibiting the phosphorylation of Akt and mTOR (Fig. Most of the anticancer research performed on the avermectin family has been focused on avermectin and IVM until now. 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 . 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]. IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. the display of certain parts of an article in other eReaders. This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. Mechanisms of IVM-induced P2 4/P2 7/NLRP3-mediated pyroptosis. Received 2020 Jun 5; Revised 2020 Sep 11; Accepted 2020 Sep 11. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. Mechanisms of IVM-induced mitochondria-mediated apoptosis. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells [52]. A drug screening study of TNBC showed that IVM could be used as a SIN3-interaction domain (SID) mimic to selectively block the interaction between SID and paired a-helix2. It has a good effect on the treatment of parasitic diseases such as river blindness, elephantiasis, and scabies. 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. PAK1 can induce MEK1/2 and ERK1/2 activation by RAF and increase PI3K/Akt signaling by PDK1. Patel H., Yacoub N., Mishra R., White A., Long Y., Alanazi S., Garrett J.T. Obviously, the existing results suggest that IVM-induced apoptosis and autophagy also exhibit cross talk. 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. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. All of the above findings indicate the potential of IVM as an autophagy activator to induce autophagy-dependent death in tumor cells. Moreover, IVM was also found to have a good inhibitory effect on the prostate cancer cell line DU145 [51]. Colorectal cancer (CRC) is the third most common cancer worldwide and still lacks effective therapy. 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]. Furthermore, ivermectin was approved for the treatment of scabies by the World Health Organization based only on 10 randomized controlled trials, including 852 patients. The chemical structures of ivermectin and other avermectin family compounds in this review. 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. In addition, IVM shows potential for clinical application in asthma [20] and neurological diseases [21]. Subsequently, the inactivation Akt/mTOR signaling cannot inhibit the formation of the Beclin-1 complex, thus inducing the formation autophagosome. 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. 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]. p21-activated kinases in cancer. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. By Laurie McGinley. ). Approximately 80% of cases of liver cancer are caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection [42]. describing ivermectin activity against SARS-CoV-2, 22 and in Brazil, in particular, the use of ivermectin . It is impossible to prove a negative, so the TOGETHER trial cannot prove that ivermectin is not useful in treating COVID. Pouliot J.F., LHeureux F., Liu Z., Prichard R.K., Georges E. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. But the result of . 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]. For example, it was found in SK-MEL-28 melanoma cells that IVM can promote apoptosis as well as autophagy [74]. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Interestingly, IVM could also show activity against BRAF wild-type melanoma cells, and its combination with dapafinib could significantly increase antitumor activity. The ePub format uses eBook readers, which have several "ease of reading" features DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. The present study represents the first study evaluating the anticancer efficacy of ivermectin in pancreatic cancer. 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. 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]. The incidence is obviously regional and familial, and Epstein-Barr virus (EBV) infection is closely related [68]. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. A study published in JAMA Network this month estimated private and Medicare plans may have paid nearly $2.5 million for ivermectin prescriptions in the week of Aug. 13 alone. 4), but there is no specific evidence to prove this speculation. Satoshi mura 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. 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 . Loibl S., Gianni L. HER2-positive breast cancer. 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 . 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]. 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]]. 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. Summary of IVM promotes programmed cell death. An early study using cells in petri dishes suggested that ivermectin has antiviral properties at very high concentrations and could inhibit the pandemic coronavirus, SARS-CoV-2. The functionality is limited to basic scrolling. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43]. Harbeck N., Penault-Llorca F., Cortes J., Gnant M., Houssami N., Poortmans P., Ruddy K., Tsang J., Cardoso F. Breast cancer. 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. 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. 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. OBrien C.A., Kreso A., Jamieson C.H. Zanconato F., Cordenonsi M., Piccolo S. YAP and TAZ: a signalling hub of the tumour microenvironment. Recently scientists have discovered that IVM has a strong anticancer effect. MDR of tumor cells is the main cause of relapses and deaths after chemotherapy [97]. Interestingly, IVM and paclitaxel have a synergistic effect on ovarian cancer, and combined treatment in in vivo experiments almost completely inhibited tumor growth. Abstract. Campbell W.C., Fisher M.H., Stapley E.O., Albers-Schonberg G., Jacob T.A. 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. The Prime Minister of Malaysia proclaimed a state of Emergency Ordinance on the 12th January 2021. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. 1-26 However, those studies have limitations that make them less definitive and informative than the studies summarized in the table. Nappi's experiment also proved that IVM combined with erlotinib to achieved a synergistic killing effect by regulating EGFR activity and in HCC827 lung cancer cells [50]. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. 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. This group explores and celebrates the successes of the repurposed drug Fenbendazole to help with cancer treatment. Melanoma is the most common malignant skin tumor with a high mortality rate. Galluzzi L., Green D.R. 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. Table 1, the main form of IVM induced programmed cell death is apoptosis. Kircik L.H., Del Rosso J.Q., Layton A.M., Schauber J. (1) Although a large number of research results indicate that IVM affects multiple signaling pathways in tumor cells and inhibits proliferation, IVM may cause antitumor activity in tumor cells through specific targets. Ravegnini G., Sammarini G., Nannini M., Pantaleo M.A., Biasco G., Hrelia P., Angelini S. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. Despite the large number of related studies, there are still some key issues that have not been resolved. I take small doses of 6-12 mg regularly (3-4 x/week) after reading about it at NIH.gov, which someone else has now posted. The combination of drugs can effectively increase efficacy, reduce toxicity or delay drug resistance. But the BBC can reveal there are serious errors in a . Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. 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 . Antoszczak M., Markowska A., Markowska J., Huczynski A. 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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