title: 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 4(4+) 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 3(2+) also exhibits free radical-mediated DNA cleavage in vitro and that 3(2+) 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 3(2+) and 4(4+) (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 3(2+) and 4(4+) 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.
authors: Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019, USA.
authors: Abhishek
authors: A
authors: Yadav
authors: Thamara
authors: T
authors: Janaratne
authors: Arthi
authors: A
authors: Krishnan
authors: Sharad S
authors: SS
authors: Singhal
authors: Sushma
authors: S
authors: Yadav
authors: Adam S
authors: AS
authors: Dayoub
authors: Doyle L
authors: DL
authors: Hawkins
authors: Sanjay
authors: S
authors: Awasthi
authors: Frederick M
authors: FM
authors: MacDonnell
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D053837:DNA Cleavage / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012428:Ruthenium / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D012428:Ruthenium