Abstract 210: Glionitrin A causes apoptosis and DNA damage-induced S phase arrest in human prostate cancer cells

Abstract

Abstract In recent study, we have isolated a new diketopiperazine disulfide, Glionitrin A (GN A), from co-culture broth of a Aspergillus fungal strain KMC901 and a Sphingomonas bacterial strain KMK001, and demonstrated anti-microbial and anti-tumor effects; however, its mechanisms of action are not understood yet. Here, we investigated anti-tumor activity of GN A and its underlying molecular mechanism in human prostate cancer DU145 cells in vitro and in vivo. GN A showed significant cytotoxicity (IC50, 1.5 μM) against DU145 cells through a caspase-8-dependent apoptotic pathway. GN A treatment (0.75 ∼ 3 μM) activated caspase-8, 9 and 3, and also increased formation of truncated BID and expression of BAX protein in a dose-dependent manner. Furthermore, GN A elevated phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM/ATR in response to DNA damage, and activated S phase checkpoint associated with ATM-Chk1/2-Cdc25A pathway. In vivo study performed in nude mice bearing xenografts of DU145 (1×107 cells/mouse, s.c.), GN A dramatically reduced the tumor volume by an average of 38.2% (5 mg/kg, p.o.) and 71.3% (10 mg/kg, p.o.) at the 27-day time point, respectively. These observations may provide aid in better understanding of the mechanism underlying the anti-tumor activity of GN A, which has the potential to be developed into an anti-prostate cancer agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 210.