Dichloroacetate, a selective mitochondria-targeting drug for oral squamous cell carcinoma: a metabolic perspective of treatment

Abstract

// Vitalba Ruggieri 1 , Francesca Agriesti 1 , Rosella Scrima 2 , Ilaria Laurenzana 1 , Donatella Perrone 2 , Tiziana Tataranni 1 , Carmela Mazzoccoli 1 , Lorenzo Lo Muzio 2 , Nazzareno Capitanio 2 , Claudia Piccoli 1, 2 1 Laboratory of Pre-Clinical and Translational Research, IRCCS, CROB, Rionero in Vulture, Potenza, Italy 2 Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy Correspondence to: Nazzareno Capitanio, e-mail: nazzareno.capitanio@unifg.it Claudia Piccoli, e-mail: claudia.piccoli@unifg.it Keywords: oral squamous cell carcinoma, dichloroacetate, oxidative metabolism, mitochondria, reactive oxygen species Received: August 31, 2014      Accepted: November 11, 2014      Published: November 25, 2014 ABSTRACT Reprogramming of metabolism is a well-established property of cancer cells that is receiving growing attention as potential therapeutic target. Oral squamous cell carcinomas (OSCC) are aggressive and drugs-resistant human tumours displaying wide metabolic heterogeneity depending on their malignant genotype and stage of development. Dichloroacetate (DCA) is a specific inhibitor of the PDH-regulator PDK proved to foster mitochondrial oxidation of pyruvate. In this study we tested comparatively the effects of DCA on three different OSCC-derived cell lines, HSC-2, HSC-3, PE15. Characterization of the three cell lines unveiled for HSC-2 and HSC-3 a glycolysis-reliant metabolism whereas PE15 accomplished an efficient mitochondrial oxidative phosphorylation. DCA treatment of the three OSCC cell lines, at pharmacological concentrations, resulted in stimulation of the respiratory activity and caused a remarkably distinctive pro-apoptotic/cytostatic effect on HSC-2 and HSC-3. This was accompanied with a large remodeling of the mitochondrial network, never documented before, leading to organelle fragmentation and with enhanced production of reactive oxygen species. The data here presented indicate that the therapeutic efficacy of DCA may depend on the specific metabolic profile adopted by the cancer cells with those exhibiting a deficient mitochondrial oxidative phosphorylation resulting more sensitive to the drug treatment.