Abstract 2971: The modulation checkpoint signaling by natural products during the DNA damage response

Abstract

Abstract ATM (ataxia telangiectasia mutated) and ATR (AT and Rad3 related) protein kinases play a crucial role in cellular DNA damage responses. The inhibition of these kinases and/or related signaling molecules lead to an abolishment of one such signal pathways termed as checkpoints. It is expected that the discovery of checkpoint modulator such as natural products will be an effective assistance of anti-cancer therapy with lower side effect. In the present study, we demonstrated the inhibitory effect of Squalene (SQ), flavonoids derived from Persimmon leaves (PL) and Schisandrin-B (SchB) on ATM/ATR-dependent checkpoint signaling pathway. The cell viability was decreased by SQ, PL or SchB treated A549 adenocarcinoma after gamma-irradiation (IR) or UV exposure. In each SQ, PL and SchB treated cells, G2/M checkpoint activity was abolished in DNA damaged cells. In vitro kinase assay revealed that PL and SchB inhibits ATM and ATR, respectively. SQ, on the other hand, showed no effect on both kinases. Interestingly, SQ increased Wip1 protein expression in unperturbed cells, and suppressed ATM activation in IR treated cells. Consistent with potential inhibition of ATM by SQ or PL, IR-induced phosphorylations of ATM effectors such as p53 (S15) and Chk1 (S317) were remarkably inhibited by the treatment of SQ or PL. SchB inhibited the specific phosphorylation of these effectors by ATR. Moreover, Xenograft and allograft studies with natural products were demonstrated that the tumor growth of both cancer cells in vivo were obviously inhibited by SQ, PL or SchB treatment. These results suggest that some natural products such as SQ, PL and SchB might be applicable to the sensitization of anti-cancer therapies such as radio- /chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2971. doi:10.1158/1538-7445.AM2011-2971