Regression of lung cancer by hypoxia-sensitizing ruthenium polypyridyl complexes

Abstract

The ruthenium (II) polypyridyl complexes (RPC), Δ-[(phen) 2Ru(tatpp)]Cl2 (Δ-[3]Cl2) and ΔΔ-[(phen)2Ru (tatpp)Ru(phen)2]Cl4 (ΔΔ-[4]Cl4, are a new generation of metal-based antitumor agents. These RPCs bind DNA via intercalation of the tatpp ligand, which itself is redox-active and is easily reduced at biologically relevant potentials. We have previously shown that RPC 44+ cleaves DNA when reduced by glutathione to a radical species and that thisDNA cleavage is potentiated under hypoxic conditions in vitro. Here, we show that 32+ also exhibits free radical-mediated DNA cleavage in vitro and that 32+ and 4 4+ both exhibit selective cytotoxicity toward cultured malignant cell lines and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs 32+ and 44+ (maximum tolerable doses ~ 65 μmol/kg) is comparable with that for cisplatin (LD50~ 57 μmol/kg), but unlike cisplatin, RPCs are generally cleared from the body unchanged via renal excretion without appreciable metabolism or nephrotoxic side effects. RPCs 32+ and 44+ are shown to suppress growth of human non-small cell lung carcinoma (~83%), show potentiated cytotoxicity in vitro under hypoxic conditions, and induce apoptosis through both intrinsic and extrinsic pathways. The novel hypoxia-enhanced DNA cleavage activity and biologic activity suggest a promising new anticancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials. ©2013 American Association for Cancer Research.