Increased sensitivity of a metastatic model of prostate cancer to a novel tetravalent platinum analog

The Prostate
Kalpana MujooZahid H Siddik

Abstract

DACH-Ac-Pt [(1R,2R-diaminocyclohexane)-(trans-diacetato)-(dichloro)-platinum(IV)] is a novel cisplatin (CDDP) analog, and we have evaluated its potential activity in human prostate cancers. Cytotoxic, biochemical pharmacologic, cell cycle, and Western blot evaluations were conducted with platinum agents to assess the role of p53 genotype and androgen-dependence status on cellular response. CDDP and DACH-Ac-Pt were equiactive against mutant p53 and androgen-independent DU-145 or PC-3 tumor cells. In wild-type p53 cells, CDDP was threefold more potent against androgen-dependent LNCaP than isogenic androgen-independent LNCaP-LN3 cells. However, the analog was equipotent in these two wild-type p53 tumor models. The greater potency of DACH-Ac-Pt than CDDP in wild-type p53 cells was not due to increased cellular drug uptake or increased adduct levels, but correlated with a lower tolerance to DNA damage. The analog also activated the p53-p21(WAF1/CIP1) signal transduction pathway more efficiently in LNCaP and LNCaP-LN3 cells, and this induced G(1)-phase cell-cycle arrest. CDDP, in contrast, activated this pathway efficiently in LNCaP cells only. In addition, and compared to CDDP, DACH-Ac-Pt was more effective in inducing Bax and incre...Continue Reading

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Citations

Dec 2, 2009·Nitric Oxide : Biology and Chemistry·Kalpana MujooFerid Murad
Aug 8, 2009·Phytochemistry·Sharon Cohen, Eliezer Flescher
Mar 12, 2009·Journal of Cellular Biochemistry·Yu ZengRobert H Getzenberg
Mar 13, 2014·ChemMedChem·Ivonne ZuravkaRichard Göttlich
Jul 23, 2016·Organic & Biomolecular Chemistry·Li-Chen HanJohn E Moses
Mar 17, 2011·Human & Experimental Toxicology·Kanittha PongjitPithi Chanvorachote

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