Synergistic antitumor interaction between valproic acid, capecitabine and radiotherapy in colorectal cancer: critical role of p53

Abstract

BackgroundRecurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy.The present study examined the combination of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) with fluoropyrimidine-based chemo-radiotherapy on colorectal cancer (CRC) cells.MethodsHCT-116 (p53-wild type), HCT-116 p53−/− (p53-null), SW620 and HT29 (p53-mutant) CRC cell lines were used to assess the antitumor interaction between VPA and capecitabine metabolite 5′-deoxy-5-fluorouridine (5′-DFUR) in combination with radiotherapy and to evaluate the role of p53 in the combination treatment. Effects on proliferation, clonogenicity and apoptosis were evaluated, along with γH2AX foci formation as an indicator for DNA damage.ResultsCombined treatment with equipotent doses of VPA and 5′-DFUR resulted in synergistic effects in CRC lines expressing p53 (wild-type or mutant). In HCT-116 p53−/− cells we observed antagonist effects. Radiotherapy further potentiated the antiproliferative, pro-apoptotic and DNA damage effects induced by 5′-DFUR/VPA combination in p53 expressing cells.ConclusionsThese results highlighted the role of VPA as valuable candidate to be added to preoperative chemo-radiotherapy in LARC. On these bases we launched the ongoing phase I/II study of VPA and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0647-5) contains supplementary material, which is available to authorized users.

Combination of 5-Fluorouracil with Epigenetic Modifiers Induces Radiosensitization, Somatostatin Receptor 2 Expression, and Radioligand Binding in Neuroendocrine Tumor Cells In Vitro

“…5-fluorouracil, DNMT inhibitors, and HDAC inhibitors radiosensitize cancer cells by suppressing DNA repair activity (22)(23)(24). Fluoropyrimidine-mediated radiosensitization is extensively used in chemoradiotherapy in solid cancers (25,26).…”

Vorinostat Potentiates 5-Fluorouracil/Cisplatin Combination by Inhibiting Chemotherapy-Induced EGFR Nuclear Translocation and Increasing Cisplatin Uptake

“…Several mechanisms of resistance to 5-fluorouracil (5FU) have been described, including high levels of thymidylate synthase (TS) expression, the essential enzyme for de novo synthesis of thymidylate and subsequently DNA synthesis, and the critical target for 5FU (5). Increased levels of TS represent one of the most common and well-described 5FU resistance mechanism (6)(7)(8)(9), also in head and neck cancer models (10), and have been correlated with poorer overall patient survival in several tumors (5). Similarly, cisplatin (CDDP) resistance mechanisms are well described and are related to cell targets, uptake, and metabolism (11).…”

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

“…Recent in vitro studies in cell lines have shown VPA to be a radiosensitizer in melanoma, breast cancer, osteosarcoma and colorectal cancer . Several in vivo and in vitro studies as well as clinical studies have also indicated that VPA has radiosensitizing effects for gliomas and is radioprotective to normal brain tissue .…”

“…124 Recent in vitro studies in cell lines have shown VPA to be a radiosensitizer in melanoma, 125 breast cancer, 126 osteosarcoma 127 and colorectal cancer. 128 Several in vivo and in vitro studies as well as clinical studies have also indicated that VPA has radiosensitizing effects for gliomas and is radioprotective to normal brain tissue. [129][130][131] A Phase II trial of concurrent radiation therapy, temozolomide and VPA in patients with glioblastoma has reported promising treatment results, in terms of improved survival and PFS.…”