Abstract 2984: Plumbagin induces p53-dependent apoptosis via generation of reactive oxygen species in human cancer cells

Abstract

Abstract Plumbagin [5-hydroxy-2-methyl-1,4-naphthaquinone], a major constituent derived from Drosera and Plumbago, displays antitumor activity both in vitro and animal models, but the molecular mechanisms of p53-mediated antitumor effects have not been clearly explored. The aim of this study is to determine the anticancer effects of plumbagin on MCF-7 (wild type p53) or Ishikawa (p53-mutant type) cells. We compared the cytotoxicity, cell cycle regulation, apoptotic cell death, and generation of intracellular reactive oxygen species (ROS) in these cancer cells. Plumbagin inhibits the growth of Ishikawa (endometrial cancer cells) and SKOV-3 cells, particularly MCF-7 cells. Plumbagin significantly increased the expression of p53 and reduced Murine Double Minute 2 (MDM2) in the MCF-7 cells. Plumbagin up-regulated the expression of p21(CIP1/WAF1) causing cell cycle arrest in the G2/M-phase by down-regulating cyclin B1 and Cdc2 in MCF-7 as well as Ishikawa cells. Plumbagin altered the ratio of Bax/Bcl-2 and cytochrome c released resulting apoptotic cell death in MCF-7 cells. Furthermore, plumbagin dramatically increased the intracellular ROS level, and pretreatment with the ROS scavenger, N-acetyl cysteine (NAC), protected against growth inhibition by plumbagin, suggesting that ROS play a pivotal role in the antitumor activity in MCF-7 cells. In mice bearing the MCF-7 cell xenografts, plumbagin significantly reduced the tumor growth and weight, without apparent side effects. In conclusion, plumbagin exerted anticancer activity in MCF-7 by generation of intracellular ROS that causes induction of apoptosis via Bcl-2/Bax pathways as well as cell cycle arrest. KEYWORDS: Plumbagin; breast cancer; apoptosis; p53, reactive oxygen species Citation Format: Umasankar De, Amit Kundu, Eunbin Kim, Jonghwan Kwack, Hyungsik Kim. Plumbagin induces p53-dependent apoptosis via generation of reactive oxygen species in human cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2984.