title: Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1.
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 MetH(2)(++)•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 MetH(2)(++)•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.
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Voltan
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Rimondi
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Melloni
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gilli
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Bertolasi
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Casciano
authors.affiliation: Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy.
authors.forename: Gian Matteo
authors.initials: GM
authors.lastname: Rigolin
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D008687:Metformin; D003999:Dichloroacetic Acid
keywords: B chronic leukemic cells; Mcl-1; apoptosis; metformin; sodium dichloroacetate