Abstract B52: Design and synthesis of GADD45β agonists for sorefenib-resistance hepatocellular carcinoma cells

Abstract

Abstract Background: Growth arrest DNA damage-inducible gene 45β (GADD45β) have been reported in regulating cellular stress response, survival, senescence, and apoptosis in cancer cells. Our previous data showed that GADD45β was induced in sorafenib-treated hepatocellular carcinoma (HCC) cell line and xenograft models. Sorafenib induction was not induced after the treatment ERK kinase inhibitor (U1206) and Raf inhibitor (ZM336372), suggesting that Raf/MEK/ERK kinase signaling pathway did not involve in induction of GADD45β by sorafenib. Methods: We have designed and synthesized a series of SC-compounds. These compounds were treated with and analyzed in terms of GADD45β expression in HCC cell lines (Huh-7, Huh7R). Also, Effects of SC-compounds and sorafenib induced cell apoptosis were evaluated. Results: In seeking new GADD45β agonists, we have screened a series of compounds with GADD45β expression assay. SC-20, a small molecule with N-(4-(quinolin-4-yloxy)phenyl)benzamide skeleton, has shown significantly in induction of GADD45β expression. Interestingly, SC-20 has no inhibition in phosphorylation of ERK, indicating that GADD45β induction by SC-20 is independent of ERK signaling pathway. In addition, SC-20 is able to inhibit HCC cell growth with MTT assay and further induce cell apoptosis. Moreover, SC-20 is able to overcome sorafenib resistance cell line by activating GADD45β expression. Conclusions: SC-20 provides a new concept that increasing GADD45β along will be applicable in sorafenib-sensitive and resistant HCC therapy. Grant support: NSC-100-2325-B-002-042, DOH100-TD-B-111-001, NSC-100-2325-B-010-007