Modulation of thymidilate synthase and p53 expression by HDAC inhibitor vorinostat resulted in synergistic antitumor effect in combination with 5FU or Raltitrexed

Abstract

Despite the introduction of several novel anticancer agents almost 50% of

colorectal cancer (CRC) patients die for cancer suggesting the necessity of new

therapeutical approaches. In this study we demonstrated that the HDAC inhibitor

vorinostat exerted potent antiproliferative effect in a panel of mut- and wt-p53 human

CRC cell lines. Moreover, in combination with 5-fluorouracil modulated by folinic acid

(5FU-FA) or with Raltitrexed (RTX), both commonly used in the treatment of this

disease, it showed a clear schedule-dependent synergistic antiproliferative interaction as

demonstrated by calculating combination indexes. Only simultaneous, or 24 hrs

pretreatment with vorinostat followed by either agent, produced synergistic effect

paralleled by evident cell cycle perturbations with major S-phase arrest. Moreover, we

provided for the first time evidences that vorinostat can overcome resistance to both

5FU and RTX. Down-modulation of TS protein induced by vorinostat within 24 hrs,

represented a key factor in enhancing the effects of both drugs in sensitive as well as

resistant tumor cells. Furthermore, p53, whose wild-type expression is critical for

sensitivity to 5FU and RTX, was up-regulated by vorinostat in wt- and down-regulated

in mut-p53 cells, suggesting an additional mechanism of the antiproliferative synergistic

interactions observed. Overall these data add new insights in the mechanism of

vorinostat antitumor effect and suggested that the association of vorinostat plus 5FU-FA

and/or RTX should be clinically explored.