The role of p53 in the cellular toxicity by active trans-platinum complexes containing isopropylamine and hydroxymethylpyridine.
Despite some initial research that reported a lack of activity of trans geometry, complexes with general formula trans-[PtCl2(L)(L')] exhibit an important cytotoxic activity in cisplatin-sensitive and resistant cell lines. Based on the proposed mechanism of action for the trans-platinum compounds, they might form DNA adducts initiating a DNA-damage response and ultimately ending in the activation of the p53 protein. In the present work, we have studied the biochemical properties of the trans-[PtCl2(isopropylamine)(L)] complexes (where L is 3- or 4-(hydroxymethyl)-pyridine) against several cell lines and the relationship between cytotoxicity and the protein p53. Both complexes showed different antitumoral properties depending on the presence or absence of protein p53 in isogenic colon carcinoma HCT116 cell lines. Cell cycle studies with the complexes in these cell lines were performed to investigate their antitumoral activity. Apoptosis was observed to be launched from G1 or G2/M accumulations. Confocal microscopy showed the different behaviour of isogenic tumoral cell lines treated with the trans-platinum complexes. Our data suggest that small differences in the carrier ligands could play an important role in the overall biological effects. The body of the research regarding structure-activity relationships such as the different position of groups in the carrier ligands will provide new rational basis for the design of new platinum antitumor drugs.
Departamento de Química Inorgánica, Universidad Autónoma de Madrid, Francisco Tomas y Valiente 7, 28049 Madrid, Spain.
Francisco J
FJ
Ramos-Lima
Victoria
V
Moneo
Adoración G
AG
Quiroga
Amancio
A
Carnero
Carmen
C
Navarro-Ranninger
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D006801:Humans; D009540:Nicotinyl Alcohol / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011437:Propylamines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D013237:Stereoisomerism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C507745:4-hydroxymethylpyridine; D009944:Organoplatinum Compounds; D011437:Propylamines; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D004247:DNA; D009540:Nicotinyl Alcohol; C035263:2-propylamine