Abstract 3834: JKA97, a novel anti-cancer candidate, induces G1 arrest via up-regulation of p21 in a p53-independent manner

Abstract

Abstract Breast cancer is one of the most commonly diagnosed cancers and the leading causes of cancer death in women worldwide. Natural product-oriented synthetic derivatives have played an important role in cancer drug discovery. JKA97, a benzylidene analog of harmine, is a novel anti-cancer candidate. The initial studies have shown its inhibitory effects on tumor growth in experimental models. However, the underlying molecular mechanisms are not fully elucidated. In this study, we determined the anti-cancer effects of JKA97 on human breast cancer in vitro and in vivo. Our data showed that, in a dose-dependent manner, JKA97 efficiently inhibited the growth and proliferation of human breast cancer cells with different p53 status, including MCF7 (p53 wild-type), MCF7 (p53 knockdown) and MDA-MB-468 (p53 mutant) cells. We also found that JKA97 induced apoptosis in human breast cancer cells independent of p53 and that JKA97 treatment resulted in G1 phase arrest in all the three breast cancer cell lines. In vivo, JKA97 significantly suppressed the growth of both breast cancer MCF7 and MDA-MB-468 xenograft tumors. Mechanistically, JKA97 modulated the levels of various cell-cycle regulators involved in G1 to S phase progression, such as p21, p27, cyclinE, and cyclinD1. Our results indicated that p21 and p27were up-regulated while cyclinE and cyclinD1 were down-regulated by JKA97 treatment. Using quantitative PCR and luciferase reporter assays, we demonstrated that the major mechanism for G1 phase arrest by JKA97 was induction of p21 at the transcriptional level, independent of p53. We further confirmed the role of p21 in JKA97-induced G1 phase arrest by using HCT116 cells with or without p21 expression. Taken together, these findings suggest that JKA97 inhibits human breast cancer by inducing cell cycle arrest through up-regulation of p21, regardless of p53 status. Considering that more than 50% human cancers have no or mutant p53 expression, our results provide a basis for further development of this compound as potential drug for breast cancer therapy. (This work was supported in part by NIH/NCI grants R01 CA112029 and R01 CA121211, R15 CA100102 and a grant (BCTR070731) from Susan G Komen for the Cure.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3834. doi:1538-7445.AM2012-3834