Document Detail


Retained platinum uptake and indifference to p53 status make novel transplatinum agents active in platinum-resistant cells compared to cisplatin and oxaliplatin.
MedLine Citation:
PMID:  22333583     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 the transplatinum compounds remained in the supernatant. We concluded that, distinct from platinum compounds currently in use, transplatinum compounds accumulate intracellularly in resistant cells at levels comparable to those in drug-sensitive cells, do not affect the cell cycle and thus retain cytotoxicity independent of p53 status and likely have cytoplasmic targets that are important in their activity.
Authors:
Robert F Murphy; Edina Komlodi-Pasztor; Robert Robey; Frank M Balis; Nicholas P Farrell; Tito Fojo
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Publication Detail:
Type:  Journal Article     Date:  2012-03-01
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-08-21     Completed Date:  2013-01-04     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  963-73     Citation Subset:  IM    
Affiliation:
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA. murphyb@mail.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / chemistry,  toxicity*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cisplatin / chemistry,  toxicity*
DNA / chemistry,  metabolism
Drug Resistance, Neoplasm / drug effects
Humans
Organoplatinum Compounds / chemistry,  toxicity*
Tumor Suppressor Protein p53 / metabolism*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Organoplatinum Compounds; 0/Tumor Suppressor Protein p53; 15663-27-1/Cisplatin; 63121-00-6/oxaliplatin; 9007-49-2/DNA
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