Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin

References

• OmuraS. Ivermectin: 25 years and still going strong. Int J Antimicrob Agents. 2008;31(2):91–98. doi:10.1016/j.ijantimicag.2007.08.02318037274
   PubMed Web of Science ®Google Scholar
• CrumpA. Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo). 2017;70(5):495–505. doi:10.1038/ja.2017.1128196978
   PubMed Web of Science ®Google Scholar
• JuarezM, Schcolnik-CabreraA, Duenas-GonzalezA. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018;8(2):317–331.29511601
   PubMed Web of Science ®Google Scholar
• GearyTG. Ivermectin 20 years on: maturation of a wonder drug. Trends Parasitol. 2005;21(11):530–532. doi:10.1016/j.pt.2005.08.01416126457
   PubMed Web of Science ®Google Scholar
• LynaghT, LynchJW. Ivermectin binding sites in human and invertebrate Cys-loop receptors. Trends Pharmacol Sci. 2012;33(8):432–441. doi:10.1016/j.tips.2012.05.00222677714
   PubMed Web of Science ®Google Scholar
• ChenIS, KuboY. Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin. J Physiol. 2018;596(10):1833–1845. doi:10.1113/JP27523629063617
   PubMed Web of Science ®Google Scholar
• ChenIS, TateyamaM, FukataY, UesugiM, KuboY. Ivermectin activates GIRK channels in a PIP2 -dependent, Gbetagamma -independent manner and an amino acid residue at the slide helix governs the activation. J Physiol. 2017;595(17):5895–5912. doi:10.1113/JP27487128715108
   PubMed Web of Science ®Google Scholar
• LaingR, GillanV, DevaneyE. Ivermectin - old drug, new tricks? Trends Parasitol. 2017;33(6):463–472. doi:10.1016/j.pt.2017.02.00428285851
   PubMed Web of Science ®Google Scholar
• KwonYJ, PetrieK, LeibovitchBA, et al. Selective inhibition of SIN3 corepressor with avermectins as a novel therapeutic strategy in triple-negative breast cancer. Mol Cancer Ther. 2015;14(8):1824–1836. doi:10.1158/1535-7163.MCT-14-0980-T26078298
   PubMed Web of Science ®Google Scholar
• KodamaM, KodamaT, NewbergJY, et al. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2017;114(35):E7301–E7310. doi:10.1073/pnas.170544111428811376
   PubMed Web of Science ®Google Scholar
• SharmeenS, SkrticM, SukhaiMA, et al. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010;116(18):3593–3603. doi:10.1182/blood-2010-01-26267520644115
   PubMed Web of Science ®Google Scholar
• HashimotoHMS, SudoT, MarutaH. Ivermectin inactivates the kinase PAK1 and blocks the PAK1dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009;3(6):3.
   Google Scholar
• DesantisV, SaltarellaI, LamanuzziA, et al. Autophagy: a new mechanism of prosurvival and drug resistance in multiple myeloma. Transl Oncol. 2018;11(6):1350–1357. doi:10.1016/j.tranon.2018.08.01430196237
   PubMed Web of Science ®Google Scholar
• BoyaP, ReggioriF, CodognoP. Emerging regulation and functions of autophagy. Nat Cell Biol. 2013;15(7):713–720. doi:10.1038/ncb278823817233
   PubMed Web of Science ®Google Scholar
• Nishimura1 HHTSHMR. The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423. Drug Discov Ther. 2010;4(1):1–4.22491145
   PubMedGoogle Scholar
• ShinojimaN, YokoyamaT, KondoY, KondoS. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy. 2014;3(6):635–637. doi:10.4161/auto.4916
   Web of Science ®Google Scholar
• DouQ, ChenHN, WangK, et al. Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt axis in breast cancer. Cancer Res. 2016;76(15):4457–4469. doi:10.1158/0008-5472.CAN-15-288727302166
   PubMed Web of Science ®Google Scholar
• WangK, GaoW, DouQ, et al. Ivermectin induces PAK1-mediated cytostatic autophagy in breast cancer. Autophagy. 2016;12(12):2498–2499. doi:10.1080/15548627.2016.123149427657889
   PubMed Web of Science ®Google Scholar
• GallardoF, MariameB, GenceR, Tilkin-MariameAF. Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth. Drug Des Devel Ther. 2018;12:2805–2814. doi:10.2147/DDDT.S172538
   PubMed Web of Science ®Google Scholar
• GallardoF, TeitiI, RochaixP, et al. Macrocyclic lactones block melanoma growth, metastases development and potentiate activity of anti– BRAF V600 inhibitors. Clini Skin Cancer. 2016;1(1):4–14.e13. doi:10.1016/j.clsc.2016.05.001
   Google Scholar
• BaiL, WangS. Targeting apoptosis pathways for new cancer therapeutics. Annu Rev Med. 2014;65:139–155. doi:10.1146/annurev-med-010713-14131024188661
   PubMed Web of Science ®Google Scholar
• ZhangY, LuoM, XuW, et al. Avermectin confers its cytotoxic effects by inducing DNA damage and mitochondria-associated apoptosis. J Agric Food Chem. 2016;64(36):6895–6902. doi:10.1021/acs.jafc.6b0281227551889
   PubMed Web of Science ®Google Scholar
• DraganovD, Gopalakrishna-PillaiS, ChenYR, et al. Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci Rep. 2015;5:16222. doi:10.1038/srep1622226552848
   PubMed Web of Science ®Google Scholar
• LiuY, FangS, SunQ, LiuB. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2016;480(3):415–421. doi:10.1016/j.bbrc.2016.10.06427771251
   PubMed Web of Science ®Google Scholar
• WangJ, XuY, WanH, HuJ. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2018;497(1):241–247. doi:10.1016/j.bbrc.2018.02.06329428725
   PubMed Web of Science ®Google Scholar
• SongD, LiangH, QuB, et al. Ivermectin inhibits the growth of glioma cells by inducing cell cycle arrest and apoptosis in vitro and in vivo. J Cell Biochem. 2019;120(1):622–633. doi:10.1002/jcb.v120.130596403
   PubMed Web of Science ®Google Scholar
• ZhangP, ZhangY, LiuK, et al. Ivermectin induces cell cycle arrest and apoptosis of HeLa cells via mitochondrial pathway. Cell Prolif. 2018;52(2):e12543.30515909
   PubMed Web of Science ®Google Scholar
• KryskoDV, GargAD, KaczmarekA, KryskoO, AgostinisP, VandenabeeleP. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012;12(12):860–875. doi:10.1038/nrc338023151605
   PubMed Web of Science ®Google Scholar
• MartinsI, WangY, MichaudM, et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 2014;21(1):79–91. doi:10.1038/cdd.2013.7523852373
   PubMed Web of Science ®Google Scholar
• PellegattiP, RaffaghelloL, BianchiG, PiccardiF, PistoiaV, Di VirgilioF. Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One. 2008;3(7):e2599. doi:10.1371/journal.pone.000259918612415
   PubMed Web of Science ®Google Scholar
• WhiteN, BurnstockG. P2 receptors and cancer. Trends Pharmacol Sci. 2006;27(4):211–217. doi:10.1016/j.tips.2006.02.00416530853
   PubMed Web of Science ®Google Scholar
• SeilM, El OuaalitiM, FontanilsU, et al. Ivermectin-dependent release of IL-1beta in response to ATP by peritoneal macrophages from P2X(7)-KO mice. Purinergic Signal. 2010;6(4):405–416. doi:10.1007/s11302-010-9205-821437011
   PubMed Web of Science ®Google Scholar
• NishioM, SugimachiK, GotoH, et al. Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc Natl Acad Sci U S A. 2016;113(1):E71–E80. doi:10.1073/pnas.151718811326699479
   PubMed Web of Science ®Google Scholar
• KangW, TongJH, ChanAW, et al. Yes-associated protein 1 exhibits oncogenic property in gastric cancer and its nuclear accumulation associates with poor prognosis. Clin Cancer Res. 2011;17(8):2130–2139. doi:10.1158/1078-0432.CCR-10-246721346147
   PubMed Web of Science ®Google Scholar
• SchlegelmilchK, MohseniM, KirakO, et al. Yap1 acts downstream of alpha-catenin to control epidermal proliferation. Cell. 2011;144(5):782–795. doi:10.1016/j.cell.2011.02.03121376238
   PubMed Web of Science ®Google Scholar
• ZhouZ, ZhangHS, ZhangZG, et al. Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1. J Cell Physiol. 2018;234:9663–9672.30362561
   PubMed Web of Science ®Google Scholar
• XiaY, ChangT, WangY, et al. YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients. PLoS One. 2014;9(3):e91770. doi:10.1371/journal.pone.009177024622501
   PubMed Web of Science ®Google Scholar
• KobayashiY, BannoK, KunitomiH, TominagaE, AokiD. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. J Gynecol Oncol. 2019;30(1):e10. doi:10.3802/jgo.2019.30.e1030479094
   PubMed Web of Science ®Google Scholar
• NambaraS, MasudaT, NishioM, et al. Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer. Oncotarget. 2017;8(64):107666–107677. doi:10.18632/oncotarget.v8i6429296196
   PubMedGoogle Scholar
• AnastasJN, MoonRT. WNT signalling pathways as therapeutic targets in cancer. Nat Rev Cancer. 2012;13:11. doi:10.1038/nrc3419
   Web of Science ®Google Scholar
• MacDonaldBT, TamaiK, HeX. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17(1):9–26. doi:10.1016/j.devcel.2009.06.01619619488
   PubMed Web of Science ®Google Scholar
• MelottiA, MasC, KuciakM, Lorente-TrigosA, BorgesI, Ruiz I AltabaA. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med. 2014;6(10):1263–1278. doi:10.15252/emmm.20140408425143352
   PubMed Web of Science ®Google Scholar
• SethC, MasC, ConodA, et al. Long-lasting WNT-TCF response blocking and epigenetic modifying activities of withanolide f in human cancer cells. PLoS One. 2016;11(12):e0168170. doi:10.1371/journal.pone.016817027973612
   PubMed Web of Science ®Google Scholar
• SladeL, PulinilkunnilT. The MiTF/TFE family of transcription factors: master regulators of organelle signaling, metabolism, and stress adaptation. Mol Cancer Res. 2017;15(12):1637–1643. doi:10.1158/1541-7786.MCR-17-032028851811
   PubMed Web of Science ®Google Scholar
• DengF, XuQ, LongJ, XieH. Suppressing ROS-TFE3-dependent autophagy enhances ivermectin-induced apoptosis in human melanoma cells. J Cell Biochem. 2018. doi:10.1002/jcb.27490
   Web of Science ®Google Scholar
• ChanJA, KrichevskyAM, KosikKS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65(14):6029–6033. doi:10.1158/0008-5472.CAN-05-013716024602
   PubMed Web of Science ®Google Scholar
• YinJ, ParkG, LeeJE, et al. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain. 2015;138(Pt 9):2553–2570. doi:10.1093/brain/awv16726121981
   PubMed Web of Science ®Google Scholar
• LeeJY, KongG. Roles and epigenetic regulation of epithelial-mesenchymal transition and its transcription factors in cancer initiation and progression. Cell Mol Life Sci. 2016;73(24):4643–4660. doi:10.1007/s00018-016-2313-z27460000
   PubMed Web of Science ®Google Scholar
• TamWL, WeinbergRA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19(11):1438–1449. doi:10.1038/nm.333624202396
   PubMed Web of Science ®Google Scholar
• SilversteinRA, EkwallK. Sin3: a flexible regulator of global gene expression and genome stability. Curr Genet. 2005;47(1):1–17. doi:10.1007/s00294-004-0541-515565322
   PubMed Web of Science ®Google Scholar
• FariasEF, PetrieK, LeibovitchB, et al. Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells. Proc Natl Acad Sci U S A. 2010;107(26):11811–11816. doi:10.1073/pnas.100673710720547842
   PubMed Web of Science ®Google Scholar
• ZhuM, LiY, ZhouZ. Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. Biochem Biophys Res Commun. 2017;492(3):373–378. doi:10.1016/j.bbrc.2017.08.09728847725
   PubMed Web of Science ®Google Scholar
• GoradelNH, MohammadiN, Haghi-AminjanH, FarhoodB, NegahdariB, SahebkarA. Regulation of tumor angiogenesis by microRNAs: state of the art. J Cell Physiol. 2019;234(2):1099–1110. doi:10.1002/jcp.2705130070704
   PubMed Web of Science ®Google Scholar
• JordanMA, WilsonL. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4(4):253–265. doi:10.1038/nrc131715057285
   PubMed Web of Science ®Google Scholar
• AshrafS, PrichardR. Ivermectin exhibits potent anti-mitotic activity. Vet Parasitol. 2016;226:1–4. doi:10.1016/j.vetpar.2016.06.01527514873
   PubMed Web of Science ®Google Scholar
• WangTG, YeM. Advances on the roles of m (6)A in tumorigenesis. Yi Chuan. 2018;40(12):1055–1065. doi:10.16288/j.yczz.18-09830559095
   PubMedGoogle Scholar
• SzakacsG, PatersonJK, LudwigJA, Booth-GentheC, GottesmanMM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5(3):219–234. doi:10.1038/nrd198416518375
   PubMed Web of Science ®Google Scholar
• GottesmanMM, FojoT, BatesSE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002;2(1):48–58. doi:10.1038/nrc70611902585
   PubMed Web of Science ®Google Scholar
• MontanariF, EckerGF. Prediction of drug-ABC-transporter interaction–recent advances and future challenges. Adv Drug Deliv Rev. 2015;86:17–26. doi:10.1016/j.addr.2015.03.00125769815
   PubMed Web of Science ®Google Scholar
• EdwardsG. Ivermectin: does P-glycoprotein play a role in neurotoxicity? Filaria J. 2003;2(Suppl 1):S8. doi:10.1186/1475-2883-2-S1-S814975065
   PubMedGoogle Scholar
• DAaLF. The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor. Anticancer Drugs. 1996;7:745–751.8949985
   PubMed Web of Science ®Google Scholar
• LiangJ, WanM, ZhangY, et al. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat Cell Biol. 2008;10(6):731–739. doi:10.1038/ncb173618454139
   PubMed Web of Science ®Google Scholar
• Dominguez-GomezG, Chavez-BlancoA, Medina-FrancoJL, et al. Ivermectin as an inhibitor of cancer stemlike cells. Mol Med Rep. 2018;17(2):3397–3403. doi:10.3892/mmr.2017.823129257278
   PubMed Web of Science ®Google Scholar
• GuzzoCA, FurtekCI, PorrasAG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122–1133. doi:10.1177/00912700240138273112362927
   PubMed Web of Science ®Google Scholar
• Reagan-ShawS, NihalM, AhmadN. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659–661. doi:10.1096/fj.07-9574LSF17942826
   PubMed Web of Science ®Google Scholar
• VerbaanderdC, MeheusL, HuysI, PantziarkaP. Repurposing Drugs in Oncology: next Steps. Trends Cancer. 2017;3(8):543–546. doi:10.1016/j.trecan.2017.06.00728780930
   PubMed Web of Science ®Google Scholar