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.
Highlights
In 2017, it is estimated that approximately 72,240 new cases of non-Hodgkins lymphoma (NHL) will be diagnosed in the United States, making NHL the 7th most common cause of cancer mortality with an estimated20,140 patient deaths this year alone [1]
We investigated the effects of single agent metformin on cellular metabolism and viability in aggressive B-cell lymphoma cell lines of varying histology and biology
We explored the effect of metformin used in combination with chemotherapy and novel targeted agents, Venetoclax, BAY-1143572 and Idelalisib, each chosen for their unique tumorigenic effects and concomitant influences on cellular metabolism
Summary
In 2017, it is estimated that approximately 72,240 new cases of non-Hodgkins lymphoma (NHL) will be diagnosed in the United States, making NHL the 7th most common cause of cancer mortality with an estimated20,140 patient deaths this year alone [1]. As www.oncotarget.com an example, patients with diffuse large B-cell lymphoma (DLBCL) who harbor a translocation at the c-MYC locus have less favorable rates of response to therapy and disease free survival compared to patients without the mutation, owing to the oncogenic effects of c-MYC [2]. Mantle cell lymphoma (MCL) represents another challenging lymphoma subtype, owing to an aggressive and variable disease course and biology, a high rate of relapse, and lack of a standardized treatment approach [4,5,6]. These subset populations are in great need of novel therapeutic strategies.
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