Combination Treatment of Renal Cell Carcinoma with Belinostat and 5-Fluorouracil: A Role for Oxidative Stress Induced DNA Damage and HSP90 Regulated Thymidine Synthase

Abstract

In combination with 5-fluorouracil the targeted inhibitor of histone deacetylase synergistically inhibited renal cancer cell growth by the blockade of thymidylate synthase induction and the induction of reactive oxygen species mediated DNA damage in vitro and in vivo. Our results suggest that combined treatment with belinostat and 5-fluorouracil may represent a promising new approach to renal cancer.

Suberoylanilide hydroxamic acid enhances chemosensitivity to 5-fluorouracil in hepatocellular carcinoma via inhibition of thymidylate synthase

“…TS expression is closely correlated with the response to both 5-FU and HDAC inhibitors in several cancer cell lines [25][26][27][28]. In the present study, TS was upregulated by 5-FU exposure alone, whereas SAHA downregulated TS expression in the presence or absence of 5-FU in a dose-dependent manner in HCC cell lines.…”

“…In addition to histones, HDAC inhibitors deacetylate many nonhistone proteins including heat shock proteins (HSPs). HDAC inhibitors upregulate the expression of acetylated HSP-90, which is an essential member of the HSP family [26,37]. HDAC6 is mostly responsible for HSP-90 deacetylation, which preserves its function [22,[43][44][45].…”

“…HDAC inhibitors have been shown to downregulate the expression of TS and overcome TS-mediated resistance caused by 5-FU in several cancer cell lines [25][26][27]. However, the relationship between HDAC inhibitors and TS in HCC has not been investigated to date.…”

“…However, the relationship between HDAC inhibitors and TS in HCC has not been investigated to date. The effect of combination treatment with 5-FU and HDAC inhibitors has been reported in lung, breast, gastric, pancreas, colon, and renal cancer cell lines [25][26][27][28], whereas little is known about its effect on HCC cell lines.…”

Crosstalk Between Decreased Anti-Oxidant and Increased Serum Angiogenesis in Renal Cell Carcinomas

“…[33][34][35] It has been reported that oxidative stress play a significant positive effects on the growth and progression of RCC. [36][37][38][39] Strong anti-oxidants are reported to have strong anticancer abilities.…”