title: Overcoming cisplatin resistance using gold(III) mimics: anticancer activity of novel gold(III) polypyridyl complexes.
abstract: Gold(III) compounds have been recognized as anticancer agents due to their structural and electronic similarities with currently employed platinum(II) species. An added benefit to gold(III) agents is the ability to overcome cisplatin resistance. This work identified four gold(III) compounds, [Au(Phen)Cl(2)]PF(6), [Au(DPQ)Cl(2)]PF(6), [Au(DPPZ)Cl(2)]PF(6), and [Au(DPQC)Cl(2)]PF(6), (Phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-d:2',3'-f]quinoxaline, DPPZ = dipyrido[3,2-a:2',3'-c] phenazine, DPQC = dipyrido[3,2-d:2',3'-f] cyclohexyl quinoxaline) that exhibited anticancer activity in both cisplatin sensitive and cisplatin resistant ovarian cancer cells. Two of these compounds, [Au(DPQ)Cl(2)]PF(6) (AQ) and [Au(DPPZ)Cl(2)]PF(6) (AZ), displayed exceptional anticancer activity and were the focus of more intensive mechanistic study. At the molecular level, AQ and AZ formed DNA adducts, generated free radicals, and upregulated pro-apoptotic signaling molecules (p53, caspases, PARP, death effectors). Taken together, these two novel gold(III) polypyridyl complexes exhibit potent antitumor activity in cisplatin resistant cancer cells. These activities may be mediated, in part, by the activation of apoptotic signaling.
authors: Department of Radiation Oncology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors: Kamalakannan
authors: K
authors: Palanichamy
authors: Nair
authors: N
authors: Sreejayan
authors: Allyn C
authors: AC
authors: Ontko
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D018736:DNA Adducts / Q000737:chemistry; D004273:DNA, Neoplasm / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006046:Gold / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D006046:Gold; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D002945:Cisplatin