Retained platinum uptake and indifference to p53 status make novel transplatinum agents active in platinum-resistant cells compared to cisplatin and oxaliplatin.

Cell Cycle
Robert F MurphyTito Fojo

Abstract

Despite the clinical success of platinum-containing drugs in the treatment of solid tumors, acquired resistance remains a major obstacle. We previously identified a group of novel transplanaramine or transplatinum compounds based on distinct activity profiles in the NCI-60 panel. In the present study, parental KB-3.1 cells with wild-type p53 and its cisplatin- and oxaliplatin-resistant sublines harboring mutant p53 proteins were used to contrast several transplatinum compounds with cisplatin and oxaliplatin. The transplatinum compounds retained cytotoxic activity in the resistant cell lines. While intracellular accumulation and DNA platination of cisplatin and oxaliplatin was decreased in the resistant cells, the transplatinum compounds both accumulated intracellularly and platinated DNA at comparable levels in all cell lines. Cytoflow analysis confirmed that cisplatin and oxaliplatin alter the cell cycle distribution and result in apoptosis; however, at comparably toxic concentrations, the transplatinum compounds did not alter the cell cycle distribution. Analysis of the cytoplasmic fraction treated with acetone showed that cisplatin and oxaliplatin readily bound to macromolecules in the pellet, whereas a larger percentage of ...Continue Reading

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Citations

Jan 22, 2015·Proceedings of the National Academy of Sciences of the United States of America·Marianne S PoruchynskyAntonio Tito Fojo
Mar 5, 2014·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Xin ZhangYa-Di Wang
Aug 12, 2014·Dalton Transactions : an International Journal of Inorganic Chemistry·Małgorzata FabijańskaJustyn Ochocki
Feb 26, 2013·Journal of the American Chemical Society·Sarah E LindahlJeffrey M Zaleski
Nov 9, 2017·Molecular Medicine Reports·Xiaoming ShiBonan Lv
Jan 24, 2020·Experimental Cell Research·James P MadiganDaniel W Rosenberg

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