Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells

// Vineela Chukkapalli 1 , Leo I. Gordon 2, 3 , Parameswaran Venugopal 1 , Jeffrey A. Borgia 4 and Reem Karmali 2, 3 1 Departments of Hematology, Oncology and Stem Cell Therapy, Rush University Medical Center, Chicago, IL, USA 2 Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 3 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 4 Departments of Pathology and Cell and Molecular Medicine, Rush University Medical Center, Chicago, IL, USA Correspondence to: Reem Karmali, email: reem.karmali@northwestern.edu Keywords: double hit lymphoma; metformin; Bcl-2 inhibitor; CDK9 inhibitor; Venetoclax Abbreviations: AMPK: Adenosine monophosphate-activated protein kinase; DLBCL: diffuse large B-cell lymphoma; CDK: cyclin-dependent kinase; DHL: double-hit lymphoma; MCL: Mantle cell lymphoma Received: October 05, 2017      Accepted: March 06, 2018      Published: April 20, 2018 ABSTRACT Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines. We demonstrated that metformin as a single agent, especially at high concentrations produced significant reductions in viability and proliferation only in Daudi and SUDHL-4 cell lines with associated alterations in mitochondrial oxidative and glycolytic metabolism. As bcl-2 proteins, cyclin dependent kinases (CDK) and phosphoinositol-3- kinase (PI3K) also influence mitochondrial physiology and metabolism with clear relevance to the pathogenesis of lymphoma, we investigated the potentiating effects of metformin when combined with novel agents Venetoclax (bcl-2 inhibitor), BAY-1143572 (CDK9 inhibitor) and Idelalisib (p110δ- PI3K inhibitor). Co-treating KPUM-UH1 and SUDHL-4 cells with 10 mM of metformin resulted in 1.4 fold and 8.8 fold decreases, respectively, in IC-50 values of Venetoclax. By contrast, 3-fold and 10 fold reduction in IC-50 values of BAY-1143572 in Daudi and Jeko-1 cells respectively was seen in the presence of 10 mM of metformin. No change in IC-50 value for Idelalisib was observed across cell lines. These data suggest that although metformin is not a potent single agent, targeting cancer metabolism with similar but more effective drugs in novel combination with either bcl-2 or CDK9 inhibitors warrants further exploration.