Abstract 2494: A non-covalent binding platinum drug, TriplatinNC, induces a G1 phase cell cycle arrest and p53-independent mechanisms of apoptosis

Abstract

Abstract TriplatinNC, is a novel trinuclear derivative of the Phase II clinical drug, BBR3464. The binding to DNA is through non-covalent (hydrogen bonding and electrostatic) interactions. The absence of substation-labile leaving groups results in insensitivity to glutathione concentration in vitro while the high (8+) charge results in enhanced cellular accumulation compared to BBR3464 and especially cisplatin. The antitumor activity of TriplatinNC was examined in vivo showing higher activity against 2008 ovarian carcinoma cells than c-DDP at the doses administered. Studies using HCT116 colon carcinoma cells have shown that TriplatinNC is cytotoxic in the presence and absence of p53. Cell cycle studies show that TriplatinNC differs from BBR3464 in inducing a G1 arrest rather than a G2 arrest in HCT116 cells. A p53-independent activation of caspase 8 and caspase 9 leading to the cleavage of caspase 3 and its downstream substrate, PARP-1, may indicate that TriplatinNC induces both intrinsic and extrinsic pathways of cell death. Our study illustrates fundamental differences in the mechanisms of action between non-covalent binding drugs like TriplatinNC and related covalent binding drugs such as c-DDP, oxaliplatin, and BBR3464. 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 2494.