title: Retained platinum uptake and indifference to p53 status make novel transplatinum agents active in platinum-resistant cells compared to cisplatin and oxaliplatin.
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 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.affiliation: Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA. murphyb@mail.nih.gov
authors.forename: Robert F
authors.initials: RF
authors.lastname: Murphy
authors.forename: Edina
authors.initials: E
authors.lastname: Komlodi-Pasztor
authors.forename: Robert
authors.initials: R
authors.lastname: Robey
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
authors.forename: Tito
authors.initials: T
authors.lastname: Fojo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000633:toxicity*; D000077150:Oxaliplatin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D004247:DNA; D002945:Cisplatin