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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).
Highlights
Recurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy
We have previously demonstrated that histone deacetylase inhibitor (HDACi), including valproic acid (VPA), synergize with fluoropyrimidines, in vitro and in vivo preclinical models of breast and colorectal cancer (CRC) cancer by downregulating thymidylate synthase (TS), the key enzyme in the mechanism of action of 5-Fluorouracil (5-FU) and by upregulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU [17,18,19]
Since p53 signaling is frequently dysregulated in CRC and the loss of a complete functional p53 is often associated with resistance to current therapies and poor prognosis, we investigated the role of p53 in the combination setting, taking advantage of four cellular models: the HCT116 p53-wild type and its p53-null subline HCT-116 p53−/−, and the HT29 and SW620 p53-mutant cell lines
Summary
Recurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy. The introduction of total mesorectal excision and preoperative radiotherapy (RT) have been revolutionary and resulted in improved local control after curative resection for rectal cancer, local relapses and distant metastasis still occur and remain a cause of recurrence worldwide [6]. This is true for the “high risk” locally advanced rectal cancer (LARC) patients, defined as the “ugly”. Several strategies have attempted to improve local control and reduce distant recurrence adding new cytotoxic agents into the standard treatment strategy, but this is still an ongoing challenging process [3]
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