Curcumin Hat Inhibition Activity Of Anti-tumor Activity

Curcumin, a polyphenol, has the ability to inhibit the proliferation of many cancer cell lines in vitro, and exhibits antitumor activity in vivo. It is suggested that curcumin has great potential in the prevention and treatment of cancer. The balance of histone acetylation and deacetylation is controlled by HAT (Histone acetyltransferase) and HDAC (Histone deacetylase). Overexpression of HAT associated with recruitment of transcription factors which will result in aberrant expression of genes, ultimately lead to cancer or other diseases. Recent study showed that curcumin significantly inhibited histone acetylation through affecting the activity of HAT in cells. We focus on the relationship between HAT inhibition of curcumin and its anti-cancer effect.In in vitro HDAC and HAT assay, curcumin did not affect HDAC activity while SAHA had strong inhibition on HDAC activity with IC₅₀ at 0.41μM. Curcumin inhibited the HAT activity with IC₅₀ at 53μM.In cytotoxicity assay, curcumin inhibited the proliferation of various cancer cell lines with IC₅₀ at 5～30μM. SAHA, a HDAC inhibitor, also inhibited the proliferation of various cancer cell lines with IC₅₀ at 0.45～3.86μM. Combination of curcumin and SAHA at 0.33μM showed an additive or antagonistic effect by method of probability sum. Combination of curcumin and SAHA at 1μM showed an antagonistie effect with Q₅₀<0.85.In western blotting, curcumin induced less histone hyperacetylation than SAHA. Combination of curcumin and SAHA yielded additive or synergistic interactions on histone hyperacetylation. p21^CIP/WAF1 mRNA expression was detected by semi-quantitative RT-PCR. Curcumin and SAHA induced p21^CIP/WAF1 mRNA expression, with maximal induction of 1.3～1.8 and 3～6 fold at higer concentration respectively. Combination of curcumin and SAHA showed an antagonistic effect on p21^CIP/WAF1 mRNA expression with coefficient of drug interaction (CDI) less than 0.85. ROS (Reactive Oxygen Species) accumulation was detected by FACS. Both curcumin and SAHA promoted intracellular ROS accumulation in cancer cell lines. Combination of curcumin and SAHA showed an antagonistic effect on ROS accumulation with CDI less than 0.85.In summary, curcumin inhibited the HAT activity and has no effect on HDAC activity in in vitro assays. At cell and gene level, Curcumin induced a little histone hyperacetylation, increased p21^CIP/WAF1 mRNA expression and promoted intracellular ROS accumulation. Furthermore, combination of curcumin and SAHA showed an additive or synergistic effect on histone hyperacetylation, but an antagonistic effect on p21^CIP/WAF1 mRNA expression and intracellular ROS accumulation. We believe that the effect of HAT inhibition and induction of histone hyperacetylation of curcumin plays little role in its anti-cancer effect.