Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin

Sevim Dalva-Aydemir, Richa Bajpai, Maylyn Martinez, Kehinde U.A. Adekola, Irawati Kandela, Changyong Wei, Seema Singhal, Jennifer E. Koblinski, Noopur S. Raje, Steven T. Rosen, Mala Shanmugam*

*Corresponding author for this work

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Purpose: We have previously demonstrated that ritonavir targeting of glycolysis is growth inhibitory and cytotoxic in a subset of multiple myeloma cells. In this study, our objective was to investigate themetabolic basis of resistance to ritonavir and to determine the utility of cotreatment with the mitochondrial complex I inhibitor metformin to target compensatory metabolism. Experimental Design: We determined combination indices for ritonavir and metformin, impact on myeloma cell lines, patient samples, and myeloma xenograft growth. Additional evaluation in breast, melanoma, and ovarian cancer cell lines was also performed. Signaling connected to suppression of the prosurvival BCL-2 family member MCL-1 was evaluated in multiple myeloma cell lines and tumor lysates. Reliance on oxidative metabolism was determined by evaluation of oxygen consumption, and dependence on glutamine was assessed by estimation of viability upon metabolite withdrawal in the context of specific metabolic perturbations. Results: Ritonavir-treated multiple myeloma cells exhibited increased reliance on glutamine metabolism. Ritonavir sensitized multiple myeloma cells to metformin, effectively eliciting cytotoxicity both in vitro and in an in vivo xenograft model of multiple myeloma and in breast, ovarian, and melanoma cancer cell lines. Ritonavir and metformin effectively suppressed AKT and mTORC1 phosphorylation and prosurvival BCL-2 family member MCL-1 expression in multiple myeloma cell lines in vitro and in vivo. Conclusions: FDA-approved ritonavir and metformin effectively target multiple myeloma cell metabolism to elicit cytotoxicity in multiple myeloma. Our studies warrant further investigation into repurposing ritonavir and metformin to target the metabolic plasticity of myeloma to more broadly target myeloma heterogeneity and prevent the reemergence of chemoresistant aggressive multiple myeloma. Clin Cancer Res; 21(5); 1161-71.

Original languageEnglish (US)
Pages (from-to)1161-1171
Number of pages11
JournalClinical Cancer Research
Volume21
Issue number5
DOIs
StatePublished - Mar 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Dalva-Aydemir, S., Bajpai, R., Martinez, M., Adekola, K. U. A., Kandela, I., Wei, C., Singhal, S., Koblinski, J. E., Raje, N. S., Rosen, S. T., & Shanmugam, M. (2015). Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin. Clinical Cancer Research, 21(5), 1161-1171. https://doi.org/10.1158/1078-0432.CCR-14-1088