Histone Deacetylase Inhibitors H40 Anti-tumor Effect And Mechanism

The balance of histone acetylation and deacetylation is controlled by HAT (histone acetyltransferase) and HDAC(histone deacetylase).Overexpression of HDAC and recruitment by transcription factors will result in aberrant expression of certain genes,ultimately lead to cancer or other diseases.Inhibition of HDACs represents a new strategy in human cancer therapy.HDACIs can induce growth arrerst,differentiation and apoptosis of tumor cells.They have shown excellent efficacy and low toxicity in preclinical studies and clinical trials.SAHA is the first HDACI approved by FDA for the treatment of cancer.H40 was designed and synthesized based on the structure of SAHA.It had strong inhibition on HDAC with IC₅₀ below 1μM,which is comparable with SAHA.It increased accumulation of hyperacetylated histones in tumors and spleens of animals as well as in cultured tumor cells.H40 exhibited potent cytotoxic effect on various cell lines which is similar to SAHA.In transplantable tumor model,H40 significantly inhibited the growth of TRAMP-C2 prostate carcinoma with the high inhibitory rate of 39.16%.While SAHA at high dose couldn't inhibit TRAMP-C2 tumor with same scheduleIn the range of 0.05μM to 0.15μM,H40 accumulated cells in G₀/G₁ phase accompanied with a decrease of cells in S phase.At 0.45μM,it also induced G₂/M arrest.H40 could induce differentiation of HL-60 cells.After treatment with H40 or SAHA,the percentages of apoptotic cells of pc-3m slightly increased,but were still below 10%.Both of the two compounds could induce dose and time dependent autophagy in pc-3m cells,which is another kind of programmed cell death.Autophagy was inducd as early as 3 hr after treatment.After treatment for 6 to 48 hr, the percentage of autophagic cells increased in a dose dependent manner.H40 induced dose-dependent expression of p21 mRNA and protein,the same results were observed with SAHA. In summary,H40 is a potent HDACI which caused inhibition of cells proliferation,cell cycle arrest,cells differentiation and autophagy,p21 is speculated to be one of the possible molecular base of its effect.