Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression
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Manuela Terranova-Barberio1, Maria Serena Roca1, Andrea Ilaria Zotti1, Alessandra Leone1, Francesca Bruzzese1, Carlo Vitagliano1, Giosuè Scogliamiglio2, Domenico Russo3, Giovanni D’Angelo3, Renato Franco2, Alfredo Budillon1, Elena Di Gennaro1
1Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
2Pathology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy
3Institute of Protein Biochemistry, National Research Council, Naples, Italy
Alfredo Budillon, e-mail: firstname.lastname@example.org
Keywords: HDAC inhibitor, valproic acid, thymidine phosphorylase, breast cancer, capecitabine
Received: July 27, 2015 Accepted: December 23, 2015 Published: December 31, 2015
The prognosis of patients with metastatic breast cancer remains poor, and thus novel therapeutic approaches are needed. Capecitabine, which is commonly used for metastatic breast cancer in different settings, is an inactive prodrug that takes advantage of elevated levels of thymidine phosphorylase (TP), a key enzyme that is required for its conversion to 5-fluororacil, in tumors. We demonstrated that histone deacetylase inhibitors (HDACi), including low anticonvulsant dosage of VPA, induced the dose- and time-dependent up-regulation of TP transcript and protein expression in breast cancer cells, but not in the non-tumorigenic breast MCF-10A cell line. Through the use of siRNA or isoform-specific HDACi, we demonstrated that HDAC3 is the main isoform whose inhibition is involved in the modulation of TP. The combined treatment with capecitabine and HDACi, including valproic acid (VPA), resulted in synergistic/additive antiproliferative and pro-apoptotic effects in breast cancer cells but not in TP-knockout cells, both in vitro and in vivo, highlighting the crucial role of TP in the synergism observed. Overall, this study suggests that the combination of HDACi (e.g., VPA) and capecitabine is an innovative antitumor strategy that warrants further clinical evaluation for the treatment of metastatic breast cancer.
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