Abstract C36: Dc917 inhibits the growth of mouse lung carcinoma both in vitro and in vivo through cell cycle arrest and ERK signaling pathway

Abstract

Abstract Background: Chemotherapeutic agents often exhibit adverse effects to patients because of their nonspecific cytotoxic effect, and therefore we have screened anticancer compounds from a natural source. Dc917, a novel derivative from a Chinese medicinal plant, exhibited specific cytotoxic effect to a panel of cancer cells but no marked impairment to human normal lung fibroblasts, and it significantly suppressed tumor growth in xenograft-bearing mice. We thus aimed to further investigate molecular mechanisms of Dc917. Methods: Cell viability and cell cycle distribution were determined by MTT assay and flow cytometry, respectively. Immunoblotting was performed to determine changes in protein levels. Knockdown of desired protein was achieved by transfection with siRNA. Meanwhile, C57BL/6 mice bearing lung carcinoma cells were used to estimate the antitumor activity in vivo. Results: Dc917-induced significant cell cycle arrest in S phase was concomitant with downregulations of cdks and cyclins, as well as upregulations of p21 and p27 expression. The complex formation between cdk2/cyclin E and cdk4/cyclin D1 was reduced; however, the recruitment of p21 or p27 to cyclin E/Cdk2 complex was increased by Dc917 incubation. In addition, Dc917-induced cell death and S phase arrest were significantly attenuated by knockdown of p21 or p27 protein. Dc917 also induced MAPK and p53 pathway, which activated p27/p21 and subsequently suppressed cyclin/cdk complexes activity, and the inhibitor of ERK (U0126) could suppress Dc917-induced cytotoxicity and upregulation of p53/p27 or p21 and egr-1/p27 or/p21 expression. Conclusions: Our preclinical data indicated that Dc917 is a potential therapeutic agent in vitro and in vivo, and further development of this agent for cancer therapy is processing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C36.