Novel histone deacetylase inhibitor CG200745 induces clonogenic cell death by modulating acetylation of p53 in cancer cells

Abstract

Histone deacetylase (HDAC) plays an important role in cancer onset and progression. Therefore, inhibition of HDAC offers potential as an effective cancer treatment regimen. CG200745, (E)-N(1)-(3-(dimethylamino)propyl)-N(8)-hydroxy-2-((naphthalene-1-loxy)methyl)oct-2-enediamide, is a novel HDAC inhibitor presently undergoing a phase I clinical trial. Enhancement of p53 acetylation by HDAC inhibitors induces cell cycle arrest, differentiation, and apoptosis in cancer cells. The purpose of the present study was to investigate the role of p53 acetylation in the cancer cell death caused by CG200745. CG200745-induced clonogenic cell death was 2-fold greater in RKO cells expressing wild-type p53 than in p53-deficient RC10.1 cells. CG200745 treatment was also cytotoxic to PC-3 human prostate cancer cells, which express wild-type p53. CG200745 increased acetylation of p53 lysine residues K320, K373, and K382. CG200745 induced the accumulation of p53, promoted p53-dependent transactivation, and enhanced the expression of MDM2 and p21(Waf1/Cip1) proteins, which are encoded by p53 target genes. An examination of CG200745 effects on p53 acetylation using cells transfected with various p53 mutants showed that cells expressing p53 K382R mutants were significantly resistant to CG200745-induced clonogenic cell death compared with wild-type p53 cells. Moreover, p53 transactivation in response to CG200745 was suppressed in all cells carrying mutant forms of p53, especially K382R. Taken together, these results suggest that acetylation of p53 at K382 plays an important role in CG200745-induced p53 transactivation and clonogenic cell death.

A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-XL

“…1), which has entered phase I clinical studies in Korea on 31 May 2010. It was reported that CG200745 induces cell death by modulating acetylation of p53 [24].…”

The histone deacetylase inhibitor trichostatin A induces cell cycle arrest and apoptosis in colorectal cancer cells via p53-dependent and -independent pathways

“…The above results suggest that TSA induce cell cycle arrest in CRC cells through p53-dependent and -independent pathway. Some HDAC inhibitors, including TSA, have been reported to induce apoptosis in cancer cells through activation of p53 by phosphorylation or acetylation (24,25), suggesting a p53-dependent apoptotic pathway by TSA. Here, we showed that TSA was effective in both p53 wild-type HCT116 cells and p53 mutant HT29 cells, indicating that TSA could induce apoptosis in CRC cells via both p53-dependent and -independent mechanisms.…”

First-in-human study of the toxicity, pharmacokinetics, and pharmacodynamics of CG200745, a pan-HDAC inhibitor, in patients with refractory solid malignancies

“…In addition to the acetylation effects on histone H3, CG200745 acetylated p53 and induced its accumulation, leading to p53 transactivation and clonogenic cell death. However, the effects of CG200745 on p53 acetylation using cells transfected with various p53 mutants showed that cells expressing p53 K382R mutants were significantly resistant to CG200745-induced clonogenic cell death compared to wild-type p53 cells [3]. CG200745 also showed increased histone H4 acetylation and apoptosis in vitro and in vivo with HCT116 colon cancer models [4].…”