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.

PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer through PIK3R3 /NF-kB/TP pathway

“…The key step in the process, which is the conversion of 5-deoxy-5-fluorouridine (5-DFUR) to active 5-FU, is catalyzed by TP. 20 Therefore, elevated levels of TP contribute to higher local concentration of the active drugs and increased sensitivity of the cells to chemotherapy of 5-FU. 21,22 Studies have reported that high level of TP expression promotes chemosensitivity and predicts a better outcome in different cancer types.…”

“…21,22 Studies have reported that high level of TP expression promotes chemosensitivity and predicts a better outcome in different cancer types. 12,20,[22][23][24] Increased level of TP was observed in different pathways, among which activation of NF-kB pathway is one of the main reason for the regulation of TP expression. 11,22 In this study, we observed that PIK3R3 could regulate the transcription level of TP by activation of the NF-kB pathway.…”

Different Schedule-Dependent Effects of Epigenetic Modifiers on Cytotoxicity by Anticancer Drugs in Colorectal Cancer Cells

“…HDAC inhibitors including TSA, SAHA and VPA were reported to show synergistic effects by pre-or cotreatment with anticancer drugs. 11,[20][21][22][23][24] The difference in the most significant combination between VPA and TSA/SAHA is not clear, but the differences in the proteome and acetylome profiling between SAHA and VPA might contribute. 25) TSA, SAHA and VPA are all HDAC inhibitors.…”

Anticonvulsant valproic acid and other short-chain fatty acids as novel anticancer therapeutics: Possibilities and challenges

“…Furthermore, the down-regulation of thymidylate synthase overexpression, which occurred in aggressive breast cancer phenotypes, could slow down the disease progression. Consequently, the combined therapy with capecitabine and VPA may result in synergistic action leading to pro-apoptotic and antiproliferative effects in breast cancer cells (21). In addition, pretreatment of breast cancer cells with VPA resulted in their notably increased sensitivity to radiotherapy (3).…”