Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1
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Rebecca Voltan1,*, Erika Rimondi2,*, Elisabetta Melloni1, Paola Gilli3, Valerio Bertolasi3, Fabio Casciano1, Gian Matteo Rigolin4, Giorgio Zauli1, Paola Secchiero1
1Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
2Department of Life Sciences, University of Trieste, Trieste, Italy
3Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
4Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy
*These authors have contributed equally to this work
Paola Secchiero, e-mail: email@example.com
Giorgio Zauli, e-mail: firstname.lastname@example.org
Keywords: metformin, sodium dichloroacetate, B chronic leukemic cells, Mcl-1, apoptosis
Received: December 04, 2015 Accepted: February 06, 2016 Published: March 03, 2016
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.
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