Development of GADD45 beta (growth arrest DNA damage-inducible gene 45 beta) agonists for the treatment of hepatocellular carcinoma (HCC)
Resource
Cancer Res., 74(19),
Journal
Cancer Res.
Journal Volume
74
Journal Issue
19
Pages
-
Date Issued
2014
Date
2014
Author(s)
Hsu, Chiun
Ou, Da-Liang
Chen, Kuen-Feng
Lin, Zhong-Zhe
Cheng, Ann-Lii
Shiau, Chung-Wai
Abstract
Abstract Induction of GADD45�] expression, which is associated with cellular stress response and apoptosis regulation, in HCC cells was found to correlate with sensitivity of sorafenib, the standard molecular targeted therapy for advanced HCC. In this study, we use this GADD45�] induction as a screening platform to identify novel agents for HCC treatment from sorafenib derivatives that lack RAF kinase inhibition activity. GADD45�] expression in Huh-7 cells was measured by quantitative RT-PCR. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry. Signal transduction pathways in cells were assessed by western blotting. In vivo anti-tumor efficacy was tested in mouse xenograft models using Huh7 and Huh7R cells, the latter had acquired resistance to sorafenib. Pharmacokinetic studies were done in Sprague-Dawley rat model. The compound SC-20, which had a N-(4-(quinolin-4-yloxy)phenyl)benzamide scaffold, showed greater GADD45�] induction than other derivatives. The nitro group on the quinolone ring of SC-20 was considered important in GADD45�] induction. SC-20 induced more prominent apoptosis and inhibition of proliferation in Huh7 cells than sorafenib, independent of MEK/ERK signaling activity in Huh7 cells. SC-20 showed more prominent GADD45�] induction and better antitumor activity than sorafenib in both Huh-7 and Huh7R xenograft models and good safety. Pharmacokinetic studies indicated that SC-20 had long plasma half-life (22.5 �� 0.51 hours), low water solubility, high (> 99%) plasma protein binding, and inhibited CYP2C9 and 2C19. GADD45�] agonists warrant further development for HCC treatment. (supported by NSC 101-2325-B-002 -039, NSC 101-2321-B-002 -014, NSC 102-2325-B-002 -038) Citation Format: Chiun Hsu, Da-Liang Ou, Kuen-Feng Chen, Zhong-Zhe Lin, Ann-Lii Cheng, Chung-Wai Shiau. Development of GADD45�] (growth arrest DNA damage-inducible gene 45 beta) agonists for the treatment of hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2522. doi:10.1158/1538-7445.AM2014-2522