Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression.

Manuela Terranova-Barberio,Elena Di Gennaro,Alessandra Leone,Giosuè Scogliamiglio,Renato Franco,Alfredo Budillon,Andrea Ilaria Zotti,Maria Serena Roca,Giovanni D’Angelo,Francesca Bruzzese,Carlo Vitagliano,Domenico Russo

doi:10.18632/oncotarget.6802

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.

Highlights

Breast cancer remains one of the most serious and common diseases and is second only to lung cancer as the leading cause of cancer death in women [1]
We demonstrated that histone deacetylase inhibitors (HDACi) with different specificity are able to modulate thymidine phosphorylase (TP) and thymidylate synthase (TS) protein levels in all breast cancer cell lines, as previously described by us and other groups in different tumor models [18, 25, 26]
We reported an innovative and rational therapeutic approach in breast cancer models based upon the combination of the HDACi Valproic acid (VPA) with capecitabine, a drug largely used to treat this disease

Summary

Introduction

Breast cancer remains one of the most serious and common diseases and is second only to lung cancer as the leading cause of cancer death in women [1]. Capecitabine, an oral prodrug of 5-fluorourcacil (5-FU), is one of the mainstays for the treatment of patients with metastatic breast cancer who are ineligible for or who are pretreated with a more intensive anthracycline- and/or taxane-based regimen. Capecitabine is approved for use in combination with docetaxel for the treatment of breast cancer patients who have received prior therapy with anthracycline, taxane, and trastuzumab. The key step, the conversion of 5’-deoxy-5-fluorouridine (5’-DFUR) into active 5-FU, occurs primarily in the tumor and is catalyzed by thymidine phosphorylase (TP). In breast cancer, TP has been considered a predictive marker for clinical response to capecitabine [6, 7], which suggests that an increase in TP expression might enhance sensitivity of tumor cells to this prodrug. The overexpression of TS has been associated with aggressive breast cancer phenotypes and a worse prognosis, in patients with breast cancer who are treated with 5-FU-based chemotherapy [8]

Methods

Results

Conclusion