Oncotarget

Research Papers:

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

Vineela Chukkapalli, Leo I. Gordon, Parameswaran Venugopal, Jeffrey A. Borgia and Reem Karmali _

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Oncotarget. 2018; 9:21166-21181. https://doi.org/10.18632/oncotarget.24989

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Abstract

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

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.


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