Gentamicin Induces Selective Toxicity in Metabolically Altered Vemurafenib-Resistant A375 Cells

Year 2024, Volume: 52 Issue: 3, 189 - 197

Fulya Dal Yöntem Gökhan Ağtürk Sinem Ayaz Şeyma Ateşoğlu Hülya Irmak Aksan Huri Bulut Handan Akçakaya Müfide Aydoğan Ahbab Ebru Hacıosmanoğlu Aldoğan

https://doi.org/10.15671/hjbc.1404345

Abstract

This study investigates the potential repurposing of gentamicin for treating drug-resistant melanoma by targeting metabolic alterations. Rising global cancer incidence and mortality, coupled with the challenge of drug resistance, necessitate novel therapeutic strategies. Initially, we addressed the influence of antibiotics on mitochondrial function, a crucial player in oxidative phosphorylation (OXPHOS). To assess this impact, we first cultured two different cancer cells, A375 and PC3, in antibiotic-free medium and showed that mitochondrial membrane potential of cells was increased in the absence of antibiotics compared to cells cultured in antibiotic containing medium. Next, we developed vemurafenib resistance in A375 cells, which were continuously cultured in antibiotic-free medium. The resistant cells exhibited a marked increase in oxygen consumption rate, indicating a shift towards OXPHOS. Finally, we treated these vemurafenib-resistant cells and noncancerous human fibroblast cells (CCD-1072Sk) with varying concentrations of gentamicin (1-1000 µM). Remarkably, gentamicin showed selective cytotoxicity towards the resistant cells while sparing non-resistant counterparts and noncancerous cells. Our findings highlight gentamicin's potential as a therapeutic agent in targeting the metabolic vulnerabilities of drug-resistant melanoma, presenting a viable new pathway in cancer treatment.

Keywords

Gentamicin, vemurafenib, melanoma, drug repurposing

Supporting Institution

Haliç University Scientific Research Projects Unit

Project Number

HBAP604-I-4

References

• F. Bray, J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, and A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 68 (2018) 394-424.
• N. Vasan, J. Baselga, and D.M. Hyman, A view on drug resistance in cancer, Nature, 575 (2019) 299-309.
• H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, and F. Bray, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA Cancer J. Clin., 71 (2021) 209-249.
• X. Guan, Cancer metastases: challenges and opportunities, Acta Pharmaceutica Sinica B, 5 (2015) 402-418.
• B. Spellberg and D.N. Gilbert, The future of antibiotics and resistance: a tribute to a career of leadership by John Bartlett, Clin. Infect. Dis., 59 Suppl 2 (2014) S71-5.
• H. Maeda and M. Khatami, Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs, Clin. Transl. Med., 7 (2018) 11.
• K.T. Flaherty, I. Puzanov, K.B. Kim, A. Ribas, G.A. McArthur, J.A. Sosman, P.J. O’Dwyer, R.J. Lee, J.F. Grippo, K. Nolop, and P.B. Chapman, Inhibition of mutated, activated BRAF in metastatic melanoma, N. Engl. J. Med., 363 (2010) 809-19.
• M.R. Girotti, F. Lopes, N. Preece, D. Niculescu-Duvaz, A. Zambon, L. Davies, S. Whittaker, G. Saturno, A. Viros, M. Pedersen, B.M. Suijkerbuijk, D. Menard, R. McLeary, L. Johnson, L. Fish, S. Ejiama, B. Sanchez-Laorden, J. Hohloch, N. Carragher, K. Macleod, G. Ashton, A.A. Marusiak, A. Fusi, J. Brognard, M. Frame, P. Lorigan, R. Marais, and C. Springer, Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma, Cancer Cell, 27 (2015) 85-96.
• A. Kreso, C.A. O’Brien, P. van Galen, O.I. Gan, F. Notta, A.M. Brown, K. Ng, J. Ma, E. Wienholds, C. Dunant, A. Pollett, S. Gallinger, J. McPherson, C.G. Mullighan, D. Shibata, and J.E. Dick, Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer, Science, 339 (2013) 543-8.
• D.A. Nathanson, B. Gini, J. Mottahedeh, K. Visnyei, T. Koga, G. Gomez, A. Eskin, K. Hwang, J. Wang, K. Masui, A. Paucar, H. Yang, M. Ohashi, S. Zhu, J. Wykosky, R. Reed, S.F. Nelson, T.F. Cloughesy, C.D. James, P.N. Rao, H.I. Kornblum, J.R. Heath, W.K. Cavenee, F.B. Furnari, and P.S. Mischel, Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA, Science, 343 (2014) 72-6.
• C. Navarro, A. Ortega, R. Santeliz, B. Garrido, M. Chacin, N. Galban, I. Vera, J.B. De Sanctis, and V. Bermudez, Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches, Pharmaceutics, 14 (2022).
• O. Warburg, On the origin of cancer cells, Science, 123 (1956) 309-14.
• O. Warburg, F. Wind, and E. Negelein, THE METABOLISM OF TUMORS IN THE BODY, J. Gen. Physiol., 8 (1927) 519-30.
• R. Moreno-Sánchez, S. Rodríguez-Enríquez, A. Marín-Hernández, and E. Saavedra, Energy metabolism in tumor cells, Febs J., 274 (2007) 1393-418.
• S.E. Weinberg and N.S. Chandel, Targeting mitochondria metabolism for cancer therapy, Nat. Chem. Biol., 11 (2015) 9-15.
• J. Hirpara, J.Q. Eu, J.K.M. Tan, A.L. Wong, M.V. Clement, L.R. Kong, N. Ohi, T. Tsunoda, J. Qu, B.C. Goh, and S. Pervaiz, Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance, Redox Biol., 25 (2019) 101076.
• L. Ippolito, A. Marini, L. Cavallini, A. Morandi, L. Pietrovito, G. Pintus, E. Giannoni, T. Schrader, M. Puhr, P. Chiarugi, and M.L. Taddei, Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells, Oncotarget, 7 (2016) 61890-61904.
• D. Ajmeera and R. Ajumeera, Drug repurposing: A novel strategy to target cancer stem cells and therapeutic resistance, Genes Dis., 11 (2024) 148-175.
• C.P. Wu, S.H. Hsiao, and Y.S. Wu, Perspectives on drug repurposing to overcome cancer multidrug resistance mediated by ABCB1 and ABCG2, Drug Resist. Updat., 71 (2023) 101011.
• M. Esner, D. Graifer, M.E. Lleonart, and A. Lyakhovich, Targeting cancer cells through antibiotic-induced mitochondrial dysfunction requires autophagy inhibition, Cancer Lett., 384 (2017) 60-69.
• R. Lamb, B. Ozsvari, C.L. Lisanti, H.B. Tanowitz, A. Howell, U.E. Martinez-Outschoorn, F. Sotgia, and M.P. Lisanti, Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease, Oncotarget, 6 (2015) 4569-84.
• M.F. Cuccarese, A. Singh, M. Amiji, and G.A. O’Doherty, A novel use of gentamicin in the ROS-mediated sensitization of NCI-H460 lung cancer cells to various anticancer agents, ACS Chem. Biol., 8 (2013) 2771-7.
• E. Dratkiewicz, A. Simiczyjew, K. Pietraszek-Gremplewicz, J. Mazurkiewicz, and D. Nowak, Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment, Int. J. Mol. Sci., 21 (2019).
• J. Hynes, L.D. Marroquin, V.I. Ogurtsov, K.N. Christiansen, G.J. Stevens, D.B. Papkovsky, and Y. Will, Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes, Toxicol. Sci., 92 (2006) 186-200.
• D.C. Wallace, Mitochondria and cancer: Warburg addressed, Cold Spring Harb Symp Quant Biol, 70 (2005) 363-74.
• S. Kalghatgi, C.S. Spina, J.C. Costello, M. Liesa, J.R. Morones-Ramirez, S. Slomovic, A. Molina, O.S. Shirihai, and J.J. Collins, Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells, Sci. Transl. Med., 5 (2013) 192ra85.
• N. Moullan, L. Mouchiroud, X. Wang, D. Ryu, E.G. Williams, A. Mottis, V. Jovaisaite, M.V. Frochaux, P.M. Quiros, B. Deplancke, R.H. Houtkooper, and J. Auwerx, Tetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research, Cell Rep., 10 (2015) 1681-1691.
• A.M. Otto, Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism, Cancer Metab., 4 (2016) 5.
• A. Viale, P. Pettazzoni, C.A. Lyssiotis, H. Ying, N. Sanchez, M. Marchesini, A. Carugo, T. Green, S. Seth, V. Giuliani, M. Kost-Alimova, F. Muller, S. Colla, L. Nezi, G. Genovese, A.K. Deem, A. Kapoor, W. Yao, E. Brunetto, Y. Kang, M. Yuan, J.M. Asara, Y.A. Wang, T.P. Heffernan, A.C. Kimmelman, H. Wang, J.B. Fleming, L.C. Cantley, R.A. DePinho, and G.F. Draetta, Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function, Nature, 514 (2014) 628-32.
• D.C. Wallace, Mitochondria and cancer, Nat. Rev. Cancer, 12 (2012) 685-98.
• T. Farge, E. Saland, F. de Toni, N. Aroua, M. Hosseini, R. Perry, C. Bosc, M. Sugita, L. Stuani, M. Fraisse, S. Scotland, C. Larrue, H. Boutzen, V. Feliu, M.L. Nicolau-Travers, S. Cassant-Sourdy, N. Broin, M. David, N. Serhan, A. Sarry, S. Tavitian, T. Kaoma, L. Vallar, J. Iacovoni, L.K. Linares, C. Montersino, R. Castellano, E. Griessinger, Y. Collette, O. Duchamp, Y. Barreira, P. Hirsch, T. Palama, L. Gales, F. Delhommeau, B.H. Garmy-Susini, J.C. Portais, F. Vergez, M. Selak, G. Danet-Desnoyers, M. Carroll, C. Recher, and J.E. Sarry, Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism, Cancer Discov., 7 (2017) 716-735.
• T.M. Ashton, W.G. McKenna, L.A. Kunz-Schughart, and G.S. Higgins, Oxidative Phosphorylation as an Emerging Target in Cancer Therapy, Clin. Cancer Res., 24 (2018) 2482-2490.
• Y.A. Shen, C.Y. Wang, Y.T. Hsieh, Y.J. Chen, and Y.H. Wei, Metabolic reprogramming orchestrates cancer stem cell properties in nasopharyngeal carcinoma, Cell Cycle, 14 (2015) 86-98.
• M. Fiorillo, R. Lamb, H.B. Tanowitz, L. Mutti, M. Krstic-Demonacos, A.R. Cappello, U.E. Martinez-Outschoorn, F. Sotgia, and M.P. Lisanti, Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells, Oncotarget, 7 (2016) 34084-99.
• W.W. Wheaton, S.E. Weinberg, R.B. Hamanaka, S. Soberanes, L.B. Sullivan, E. Anso, A. Glasauer, E. Dufour, G.M. Mutlu, G.S. Budigner, and N.S. Chandel, Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis, Elife, 3 (2014) e02242.
• T. Onoda, T. Ono, D.K. Dhar, A. Yamanoi, and N. Nagasue, Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells, Int. J. Cancer, 118 (2006) 1309-15.