Abstract
Metformin and the mitochondrial targeting dichloroacetate (DCA) have recently received attention due to their ability to inhibit anaerobic glycolysis, which renders most cancer cells resistant to apoptosis induction. We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients' cells and its anti-leukemic activity was enhanced when used in combination with DCA. In order to overcome the problems of poor bioavailability and cellular uptake, which limit DCA efficacy, we have designed and synthetized cocrystals consisting of Metformin and DCA (Met-DCA) at different stoichiometric ratios. Of note, the MetH2++•2DCA− cocrystal exhibited enhanced in vitro anti-leukemic activity, with respect to the treatment with the mix consisting of Metformin plus DCA. In particular, the treatment with the cocrystal MetH2++•2DCA− induced a synergistic apoptotic cell death coupled to a marked down-modulation of the anti-apoptotic Mcl-1 protein. Taken together, our data emphasize that innovative compounds based on Metformin-DCA combination merit to be further evaluated as chemotherapeutic agents for the treatment of B-CLL.
Highlights
Most cancers are characterized by enhanced glycolytic flux for ATP production, enhanced glucose to lactate conversion and reduced mitochondrial oxidative phosphorylation, even under aerobic conditions [1,2,3]
We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients’ cells and its anti-leukemic activity was enhanced when used in combination with DCA
The Met-DCA cocrystal was effective as pro-apoptotic molecule resulting in a significant (p
Summary
Most cancers are characterized by enhanced glycolytic flux for ATP production, enhanced glucose to lactate conversion and reduced mitochondrial oxidative phosphorylation, even under aerobic conditions [1,2,3] This cancer-specific metabolic remodeling can be reversed by dichloroacetate (DCA), a mitochondriatargeting small molecule able to penetrate most tissues after oral administration [4]. Among the great variety of anti-cancer drugs, another inexpensive and safe drug, which has recently revealed a potential anti-leukemic activity, is Metformin [11,12,13,14] This molecule represents the most commonly prescribed drug for type 2 diabetes mellitus [11]. DCA and Metformin share several mechanisms, potentially involved in their anticancer activity, by disrupting mitochondrial respiratory chain complex and decreasing the ATP synthesis [19]
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