Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells
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Vineela Chukkapalli1, Leo I. Gordon2,3, Parameswaran Venugopal1, Jeffrey A. Borgia4 and Reem Karmali2,3
1Departments of Hematology, Oncology and Stem Cell Therapy, Rush University Medical Center, Chicago, IL, USA
2Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
3Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
4Departments of Pathology and Cell and Molecular Medicine, Rush University Medical Center, Chicago, IL, USA
Reem Karmali, email: firstname.lastname@example.org
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
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.
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