Overcoming cisplatin resistance using gold(III) mimics: anticancer activity of novel gold(III) polypyridyl complexes |
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Authors: | Palanichamy Kamalakannan Sreejayan Nair Ontko Allyn C |
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Institution: | a Department of Radiation Oncology, The Ohio State University Medical Center, Columbus, OH 43210, USAb School of Pharmacy, Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USAc Department of Chemistry and Physics, Arkansas State University, P.O. Box 419, State University, AR 72467, USA |
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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)Cl2]PF6, Au(DPQ)Cl2]PF6, Au(DPPZ)Cl2]PF6, and Au(DPQC)Cl2]PF6, (Phen = 1,10-phenanthroline, DPQ = dipyrido3,2-d:2′,3′-f]quinoxaline, DPPZ = dipyrido3,2-a:2′,3′-c] phenazine, DPQC = dipyrido3,2-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)Cl2]PF6 (AQ) and Au(DPPZ)Cl2]PF6 (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. |
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Keywords: | Gold(III) Au(III) Polypyridyl Cellular uptake DNA binding affinity Anticancer |
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