title: Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin.
abstract: OBJECTIVE
  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 the metabolic basis of resistance to ritonavir and to determine the utility of cotreatment with the mitochondrial complex I inhibitor metformin to target compensatory metabolism.
  
  
  METHODS
  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.
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.
authors.forename: Sevim
authors.initials: S
authors.lastname: Dalva-Aydemir
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Richa
authors.initials: R
authors.lastname: Bajpai
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.
authors.forename: Maylyn
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.
authors.forename: Kehinde U A
authors.initials: KU
authors.lastname: Adekola
authors.affiliation: Chemistry Life Processes Institute, Northwestern University, Chicago, Illinois.
authors.forename: Irawati
authors.initials: I
authors.lastname: Kandela
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Changyong
authors.initials: C
authors.lastname: Wei
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois. Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Seema
authors.initials: S
authors.lastname: Singhal
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Koblinski
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Noopur S
authors.initials: NS
authors.lastname: Raje
authors.affiliation: City of Hope, Duarte, California.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia. mala.shan@emory.edu.
authors.forename: Mala
authors.initials: M
authors.lastname: Shanmugam
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors; D015870:Gene Expression; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010101:Oxygen Consumption / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051275:Glucose Transporter Type 4; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D005973:Glutamine; D008687:Metformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D042967:Electron Transport Complex I; D019438:Ritonavir