title: Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression.
abstract: 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.
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Terranova-Barberio
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Roca
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Andrea Ilaria
authors.initials: AI
authors.lastname: Zotti
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Leone
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bruzzese
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Vitagliano
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Giosuè
authors.initials: G
authors.lastname: Scogliamiglio
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.affiliation: Institute of Protein Biochemistry, National Research Council, Naples, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: D'Angelo
authors.affiliation: Pathology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Budillon
authors.affiliation: Experimental Pharmacology Unit, Istituto Nazionale Tumori Fondazione G. Pascale - IRCCS, Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Di Gennaro
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D000069287:Capecitabine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000927:Anticonvulsants; D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D014635:Valproic Acid; D000069287:Capecitabine; D013939:Thymidine Phosphorylase
keywords: HDAC inhibitor; breast cancer; capecitabine; thymidine phosphorylase; valproic acid