Targeting the Metabolic Plasticity of Multiple Myeloma with FDA-Approved Ritonavir and Metformin

• Type of Material: Article
• Authors: Sevim Dalva-Aydemir, Northwestern University; Richa Bajpai, Emory University; Maylyn Martinez, Northwestern University; Kehinde U. A. Adekola, Northwestern University; Irawati Kandela, Northwestern University; Changyong Wei, Emory University; Seema Singhal, Northwestern University; Jennifer E. Koblinski, Northwestern University; Noopur S. Raje, Harvard University; Steven T. Rosen, City of Hope National Medical Center; Malathy Shanmugam, Emory University
• Language: English
• Date: 2015-03-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2014 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-14-1088
• Title of Journal or Parent Work: Clinical Cancer Research
• ISSN: 1078-0432
• Volume: 21
• Issue: 5
• Start Page: 1161
• End Page: 1171
• Grant/Funding Information: All animal studies were performed by Dr. Irawati Kandela and IHC staining by Andrey Ugolkov at the Northwestern University Center for Developmental Therapeutics core funded by the Robert H. Lurie Cancer Center, generously supported by NCI CCSG P30 CA060553 core grant.; This work was supported by Robert H.L.C.C center gift fund (to S.T. Rosen), Wendy Will Case Cancer Foundation grant SP0012544 (to M. Shanmugam), American Cancer Society (IL division grant #188679; to M. Shanmugam), and the American Cancer Society (Research scholar grant RSG-11-254-01-CSM; to M. Shanmugam).
• Keywords: SURVIVAL; GLUCOSE-METABOLISM; Oncology; HIV PROTEASE INHIBITORS; KINASE; Life Sciences & Biomedicine; THERAPY; Science & Technology; RESPIRATORY-CHAIN; INSULIN-RESISTANCE; CANCER-CELLS; MCL-1; APOPTOSIS
• Research Categories: Health Sciences, Oncology

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.