PT - JOURNAL ARTICLE AU - Yadav, Abhishek AU - Janaratne, Thamara AU - Krishnan, Arthi AU - Singhal, Sharad S AU - Yadav, Sushma AU - Dayoub, Adam S AU - Hawkins, Doyle L AU - Awasthi, Sanjay AU - MacDonnell, Frederick M TI - Regression of Lung Cancer by Hypoxia Sensitizing Ruthenium Polypyridyl Complexes DP - 2013 Feb 26 TA - Molecular Cancer Therapeutics 4099 - http://mct.aacrjournals.org/content/early/2013/02/26/1535-7163.MCT-12-1130.short 4100 - http://mct.aacrjournals.org/content/early/2013/02/26/1535-7163.MCT-12-1130.full AB - The ruthenium (II) polypyridyl complexes (RPCs) 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 anti-tumor agents. These RPCs bind DNA via intercalation of the tatpp ligand which itself is redox-active and 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 this DNA 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 44+ both exhibit selective cytotoxicity towards cultured malignant cell lines, and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs 32+ and 44+ (maximum tolerable doses (MTD's) ~ 65 μmol/kg) is comparable with that for cisplatin (LD50 ~57 μmol/kg) but unlike cisplatin, RPC's are generally cleared from the body unchanged via renal excretion without appreciable metabolism or nephrotoxic side effects. RPCs 32+ and 44+ are demonstrated 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 biological activity suggest a promising new anti-cancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials.