Combination of metformin/efavirenz/fluoxetine exhibits profound anticancer activity via a cancer cell-specific ROS amplification

References

• Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiological Reviews. 2007;87(1):245–13. doi:10.1152/physrev.00044.2005.
   PubMed Web of Science ®Google Scholar
• Wang J, Yi J. Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biology & Therapy. 2008;7(12):1875–1884. doi:10.4161/cbt.7.12.7067.
   PubMed Web of Science ®Google Scholar
• Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, Castoria G, Migliaccio A. ROS in cancer therapy: the bright side of the moon. Experimental & Molecular Medicine. 2020;52(2):192–203. doi:10.1038/s12276-020-0384-2.
   PubMed Web of Science ®Google Scholar
• Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Reviews Drug Discovery. 2009;8(7):579–591. doi:10.1038/nrd2803.
   PubMed Web of Science ®Google Scholar
• Li X, Hou Y, Zhao J, Li J, Wang S, Fang J. Combination of chemotherapy and oxidative stress to enhance cancer cell apoptosis. Chemical Science. 2020;11(12):3215–3222. doi:10.1039/C9SC05997K.
   PubMed Web of Science ®Google Scholar
• Shi -Z-Z, Fan Z-W, Chen Y-X, Xie X-F, Jiang W, Wang W-J, Qiu Y-T, Bai J. Ferroptosis in carcinoma: regulatory mechanisms and new method for cancer therapy. Onco Targets Ther. 2019;12:11291–11304. doi:10.2147/OTT.S232852.
   PubMed Web of Science ®Google Scholar
• Kim SJ, Kim HS, Seo YR. Understanding of ROS-inducing strategy in anticancer therapy. Oxidative Medicine and Cellular Longevity. 2019;2019:5381692. doi:10.1155/2019/5381692.
   PubMed Web of Science ®Google Scholar
• Waheed U, Arshad M, Raza M. ROS-modulated therapeutic approaches in cancer treatment. Journal of Cancer Research and Clinical Oncology. 2017;143(1):143. doi:10.1007/s00432-016-2261-x.
   PubMedGoogle Scholar
• Warkad MS, Kim C-H, Kang B-G, Park S-H, Jung J-S, Feng J-H, Inci G, Kim S-C, Suh H-W, Lim SS, et al. Metformin-induced ROS upregulation as amplified by apigenin causes profound anticancer activity while sparing normal cells. Scientific Reports. 2021;11(1):14002. doi:10.1038/s41598-021-93270-0.
   PubMed Web of Science ®Google Scholar
• Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang -T-T, Bos JL, Medema RH, Burgering BMT, et al. 2002. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 419(6904):316–321. doi:10.1038/nature01036.
   PubMed Web of Science ®Google Scholar
• Libina N, Berman JR, Kenyon C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell. 2003;115(4):489–502. doi:10.1016/S0092-8674(03)00889-4.
   PubMed Web of Science ®Google Scholar
• Nemoto S, Finkel T. Redox regulation of forkhead proteins through a p66shc -dependent signaling pathway. Science. 2002;295(5564):2450–2452. doi:10.1126/science.1069004.
   PubMed Web of Science ®Google Scholar
• Alcendor RR, Gao S, Zhai P, Zablocki D, Holle E, Yu X, Tian B, Wagner T, Vatner SF, Sadoshima J, et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circulation Research. 2007;100(10):1512–1521. doi:10.1161/01.RES.0000267723.65696.4a.
   PubMed Web of Science ®Google Scholar
• Fadaka A, Ajiboye B, Ojo O, Adewale O, Olayide I, Emuowhochere R. Biology of glucose metabolization in cancer cells. Journal of Oncological Sciences. 2017;3(2):45–51. doi:10.1016/j.jons.2017.06.002.
   Google Scholar
• Hartwig J, Loebel M, Steiner S, Bauer S, Karadeniz Z, Roeger C, Skurk C, Scheibenbogen C, Sotzny F. Metformin attenuates ROS via FOXO3 activation in immune cells. Frontiers in Immunology. 2021;12:581799. doi:10.3389/fimmu.2021.581799.
   PubMed Web of Science ®Google Scholar
• Schexnayder C, Broussard K, Onuaguluchi D, Poché A, Ismail M, McAtee L, Llopis S, Keizerweerd A, McFerrin H, Williams C, et al. Metformin inhibits migration and invasion by suppressing ROS production and COX2 expression in MDA-MB-231 breast cancer cells. Int J Mol Sci. 2018;19(11):3692. doi:10.3390/ijms19113692.
   PubMed Web of Science ®Google Scholar
• Mogavero A, Maiorana MV, Zanutto S, Varinelli L, Bozzi F, Belfiore A, Volpi CC, Gloghini A, Pierotti MA, Gariboldi M, et al. Metformin transiently inhibits colorectal cancer cell proliferation as a result of either AMPK activation or increased ROS production. Sci Rep. 2017;7(1):15992. doi:10.1038/s41598-017-16149-z.
   PubMedGoogle Scholar
• Kheirandish M, Mahboobi H, Yazdanparast M, Kamal W, Kamal MA. Anti-cancer effects of metformin: recent evidences for its role in prevention and treatment of cancer. Current Drug Metabolism. 2018;19(9):793–797. doi:10.2174/1389200219666180416161846.
   PubMed Web of Science ®Google Scholar
• Zhao B, Luo J, Yu T, Zhou L, Lv H, Shang P. Anticancer mechanisms of metformin: a review of the current evidence. Life Sciences. 2020;254:117717. DOI: 10.1016/j.lfs.2020.117717.
   PubMed Web of Science ®Google Scholar
• Di Matteo S, Nevi L, Overi D, Landolina N, Faccioli J, Giulitti F, Napoletano C, Oddi A, Marziani AM, Costantini D, et al. Metformin exerts anti-cancerogenic effects and reverses epithelial-to-mesenchymal transition trait in primary human intrahepatic cholangiocarcinoma cells. Sci Rep. 2021;11(1):2557. doi:10.1038/s41598-021-81172-0.
   PubMed Web of Science ®Google Scholar
• Grossi V, Fasano C, Celestini V, Lepore Signorile M, Sanese P. Chasing the FOXO3: insights into its new mitochondrial lair in colorectal cancer landscape. Cancers. 2019;12(1):11. doi:10.3390/cancers12010011.
   PubMedGoogle Scholar
• Sena P, Mancini S, Benincasa M, Mariani F, Palumbo C, Roncucci L. Metformin induces apoptosis and alters cellular responses to oxidative stress in Ht29 colon cancer cells: preliminary findings. International Journal of Molecular Sciences. 2018;19(5):1478. doi: 10.3390/ijms19051478.
   PubMed Web of Science ®Google Scholar
• Gao ZY, Liu Z, Bi MH, Zhang JJ, Han ZQ, Han X, WANG H-Y, SUN G-P, LIU H. Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Experimental and Therapeutic Medicine. 2016;11(5):1700–1706. doi:10.3892/etm.2016.3143.
   PubMed Web of Science ®Google Scholar
• Li Y, Wang M, Zhi P, You J, Gao J-Q. Metformin synergistically suppress tumor growth with doxorubicin and reverse drug resistance by inhibiting the expression and function of P-glycoprotein in MCF7/ADR cells and xenograft models. Oncotarget. 2018;9(2):2158. doi:10.18632/oncotarget.23187.
   PubMedGoogle Scholar
• Ko E, Baek S, Kim J, Park D, Lee Y. Antitumor activity of combination therapy with metformin and trametinib in non-small cell lung cancer cells. Development & Reproduction. 2020;24(2):113–123. doi:10.12717/DR.2020.24.2.113.
   PubMedGoogle Scholar
• Guo L, Cui J, Wang H, Medina R, Zhang S, Zhang X, Zhuang Z, Lin Y. Metformin enhances anti-cancer effects of cisplatin in meningioma through AMPK-mTOR signaling pathways. Molecular Therapy - Oncolytics. 2021;20:119–131. doi:10.1016/j.omto.2020.11.004.
   PubMed Web of Science ®Google Scholar
• Nachega JB, Hislop M, Dowdy DW, Gallant JE, Chaisson RE, Regensberg L, Maartens G. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS (London, England). 2008;22(16):2117–2125. doi:10.1097/QAD.0b013e328310407e.
   PubMed Web of Science ®Google Scholar
• Maggiolo F. Efavirenz: a decade of clinical experience in the treatment of HIV. The Journal of Antimicrobial Chemotherapy. 2009;64(5):910–928. doi:10.1093/jac/dkp334.
   PubMed Web of Science ®Google Scholar
• Tebas P, Sension M, Arribas J, Duiculescu D, Florence E, Hung CC, Wilkin T, Vanveggel S, Stevens M, Deckx H, et al. Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-Infected adults treated with rilpivirine or Efavirenz for 96 weeks in the ECHO and THRIVE trials. Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America. 2014;59(3):425–434. doi:10.1093/cid/ciu234.
   PubMed Web of Science ®Google Scholar
• Lee KK, Boelsterli UA. Bypassing the compromised mitochondrial electron transport with methylene blue alleviates efavirenz/isoniazid-induced oxidant stress and mitochondria-mediated cell death in mouse hepatocytes. Redox Biology. 2014;2:599–609. doi:10.1016/j.redox.2014.03.003.
   PubMed Web of Science ®Google Scholar
• Apostolova N, Gomez-Sucerquia LJ, Moran A, Alvarez A, Blas-Garcia A, Esplugues JV. Enhanced oxidative stress and increased mitochondrial mass during efavirenz-induced apoptosis in human hepatic cells. Br J Pharmacol. 2010;160(8):2069–2084. doi:10.1111/j.1476-5381.2010.00866.x.
   PubMed Web of Science ®Google Scholar
• Hecht M, Erber S, Harrer T, Klinker H, Roth T, Parsch H, Fiebig N, Fietkau R, Distel LV. Efavirenz has the highest anti-proliferative effect of non-nucleoside Reverse transcriptase inhibitors against pancreatic cancer cells. PLoS One. 2015;10(6):e0130277. doi:10.1371/journal.pone.0130277. PMID: 26086472; PMCID: PMC4473268.
   PubMed Web of Science ®Google Scholar
• Brüning A, Jückstock J, Kost B, Tsikouras P, Weissenbacher T, Mahner S, Mylonas I. Induction of DNA damage and apoptosis in human leukemia cells by efavirenz. Oncol Rep. 2017;37(1):617–621. doi:10.3892/or.2016.5243.
   PubMed Web of Science ®Google Scholar
• Mun A-R, Lee S-J, Kim G-B, Kang H-S, Kim J-S, Kim S-J. Fluoxetine-induced apoptosis in hepatocellular carcinoma cells. Anticancer Research. 2013;33(9):3691–3697.
   PubMed Web of Science ®Google Scholar
• Po WW, Wynn Thein PPK, Khing TM, Han KWW, Park CH, Sohn UD, Sohn UD. Fluoxetine simultaneously induces both apoptosis and autophagy in human gastric adenocarcinoma cells. Biomolecules & Therapeutics. 2020;28(2):202. doi:10.4062/biomolther.2019.103.
   PubMed Web of Science ®Google Scholar
• Hsu L-C, H-F T, Hsu F-T, Yueh P-F, Chiang I-T. Beneficial effect of fluoxetine on anti-tumor progression on hepatocellular carcinoma and non-small cell lung cancer bearing animal model. Biomedicine & Pharmacotherapy. 2020;126:110054. doi:10.1016/j.biopha.2020.110054.
   PubMed Web of Science ®Google Scholar
• Gu Y, Zhang B, Gu G, Yang X, Qian Z. Metformin increases the chemosensitivity of pancreatic cancer cells to gemcitabine by reversing EMT through regulation DNA methylation of miR-663. Onco Targets Ther. 2020;13:10417. doi:10.2147/OTT.S261570.
   PubMed Web of Science ®Google Scholar
• Khing TM, Po WW, Sohn UD. Fluoxetine enhances anti-tumor activity of paclitaxel in gastric adenocarcinoma cells by triggering apoptosis and necroptosis. Anticancer Research. 2019;39(11):6155–6163. doi:10.21873/anticanres.13823.
   PubMed Web of Science ®Google Scholar
• Kannen V, Hintzsche H, Zanette DL, Silva WA Jr., Garcia SB, Waaga-Gasser AM, Stopper H. Antiproliferative effects of fluoxetine on colon cancer cells and in a colonic carcinogen mouse model. PloS one. 2012;7(11):e50043. doi:10.1371/journal.pone.0050043.
   PubMed Web of Science ®Google Scholar
• Jahanafrooz Z, Mosafer J, Akbari M, Hashemzaei M, Mokhtarzadeh A, Baradaran B. Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment. Journal of Cellular Physiology. 2020;235(5):4153–4166. doi:10.1002/jcp.29337.
   PubMed Web of Science ®Google Scholar
• Vial G, Detaille D, Guigas B. Role of mitochondria in the Mechanism(s) of action of metformin. Frontiers in Endocrinology. 2019;10:294. doi:10.3389/fendo.2019.00294.
   PubMed Web of Science ®Google Scholar
• Curti C, Mingattao FE, Polizello A, Galastri LO, Uyemura SA, Santos AC. Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0-ATPase activity. Molecular and Cellular Biochemistry. 1999;199(1/2):103–109. doi:10.1023/A:1006912010550.
   PubMed Web of Science ®Google Scholar
• Hroudová J, Fišar Z. In vitro inhibition of mitochondrial respiratory rate by antidepressants. Toxicology Letters. 2012;213(3):345–352. doi:10.1016/j.toxlet.2012.07.017.
   PubMed Web of Science ®Google Scholar
• Purnell PR, Fox HS. Efavirenz induces neuronal autophagy and mitochondrial alterations. Journal of Pharmacology and Experimental Therapeutics. 2014;351(2):250–258. doi:10.1124/jpet.114.217869.
   PubMed Web of Science ®Google Scholar
• Funes HA, Blas-Garcia A, Esplugues JV, Apostolova N. Efavirenz alters mitochondrial respiratory function in cultured neuron and glial cell lines. Journal of Antimicrobial Chemotherapy. 2015;70(8):2249–2254. doi:10.1093/jac/dkv098.
   PubMed Web of Science ®Google Scholar
• Leavesley HB, Li L, Prabhakaran K, Borowitz JL, Isom GE. Interaction of cyanide and nitric oxide with cytochrome c oxidase: implications for acute cyanide toxicity. Toxicological Sciences. 2008;101(1):101–111. doi:10.1093/toxsci/kfm254.
   PubMed Web of Science ®Google Scholar
• Woo SH, Park I-C, Park M-J, Lee H-C, Lee S-J, Chun Y-J, Lee S-H, Hong S-I, Rhee CH. Arsenic trioxide induces apoptosis through a reactive oxygen species-dependent pathway and loss of mitochondrial membrane potential in HeLa cells. International Journal of Oncology. 2002;21(1):57–63.
   PubMed Web of Science ®Google Scholar
• Ko Y, Choi A, Lee M, Lee JA. Metformin displays in vitro and in vivo antitumor effect against osteosarcoma. Korean Journal of Pediatrics. 2016;59(9):374. doi:10.3345/kjp.2016.59.9.374.
   PubMedGoogle Scholar
• Xia C, He Z, Liang S, Chen R, Xu W, Yang J, Xiao G, Jiang S. Metformin combined with nelfinavir induces SIRT3/mROS-dependent autophagy in human cervical cancer cells and xenograft in nude mice. European Journal of Pharmacology. 2019;848:62–69.doi: 10.1016/j.ejphar.2019.01.045.
   PubMed Web of Science ®Google Scholar
• Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods. 1983;65(1–2):55–63. doi:10.1016/0022-1759(83)90303-4.
   PubMed Web of Science ®Google Scholar