CG-200745, a HDAC Inhibitor, Induces the Accumulation of p53

Histone deacetylase (HDAC) inhibits are considered to be promising agents that can be used as treatments for cancer.

CG-200745 is a novel and potent hydroxamate-based pan-HDAC inhibitor.

CG 200745 a HDAC Inhibitor Induces the Accumulation of p53 2019 10 14 - CG-200745, a HDAC Inhibitor, Induces the Accumulation of p53

CG-200745 has the hydroxamic acid moiety to bind zinc at the bottom of the catalytic pocket. We will introduce its anti-tumorigenic property here.

Firstly, the Authors analyze CG-200745 inhibitory activity in LNCaP, DU145, and PC3 cells. CG-200745 inhibits the deacetylation of histone H3 and tubulin in a time- and dose-dependent manner at 1 or 10 μM.

The result shows that CG200745 decreases LNCaP, DU145, and PC3 cell viability in a dose-dependent manner for 48 hours. CG-200745 inhibits cell Growth with IC50 values of 1.7 μM in LNCaP cells, 2.2 μM in DU145 cells, and 8.4μM in PC3 cells.

Next, they assess the CG-200745 effect on apoptotic signals of prostate cancer cells. CG-200745, 24 hours, increases in both G2-M and hypodiploid sub-G1 population by flow cytometry. These results indicate that CG-200745 induces apoptosis.

Besides, they identify the mechanisms of apoptosis of CG200745 in prostate cancer cell lines.

CG-200745 results in the activation of caspase-9 and −3 at 10 μM. CG-200745 also activates caspase-8, an enzyme with a role in the extrinsic apoptotic pathway. Collectively, CG200745 kills cancer cells by inducing both extrinsic and intrinsic apoptosis.

Next, we examined the effect of CG200745 on cell death induced by docetaxel in DU145 cells in vitro and in vivo.

CG200745 combines with docetaxel shows synergistic cytotoxicity in DU145 cells. Meanwhile, The combination treatment increases the apoptotic sub-G1 population, caspase activation, and tubulin acetylation. Moreover, CG200745 and docetaxel decrease levels of the anti-apoptotic Bcl-2 family proteins (Mcl-1 and Bcl-XL).

Lastly, the authors access the CG200745 effect on DU145 Xenografts.

They subcutaneously inject nude mice with DU145 cells. Then, they maintain them until the volume of tumors reached 100 mm3. The results show that CG200745 single can reduce tumor volume at 30 mg/kg. But CG200745 (30mg/kg) and docetaxel (10 mg/kg) combined treatment reduces tumor volume more obviously. And, compared to a single treatment, it does not affect body weight.

In summary, the antitumor effect and the mechanism are demonstrated in this article. CG-200745 inhibits DU145 cell growth and induces apoptosis in vitro and inhibits tumor growth in DU145 xenograft in vivo.

Hwang JJ, et al. Invest New Drugs. 2012 Aug;30(4):1434-42.