title: Role of apoptosis and apoptosis-related proteins in the cisplatin-resistant phenotype of human tumor cell lines.
abstract: Since apoptosis is the primary mode of cell death induced by cisplatin, the role of apoptosis and apoptosis-related gene products in cisplatin resistance was investigated in four human cisplatin-resistant cell lines of different tumour type. A common feature of the resistant sublines was a reduced susceptibility to drug-induced apoptosis compared to parental sensitive lines. Loss of wild-type p53 function was not a general event associated with the development of drug resistance. An increased bcl-2 expression was found in resistant cells characterized by mutant p53 (A431/Pt and IGROV-1/Pt), whereas in osteosarcoma (U2-OS/Pt) and in ovarian carcinoma (A2780/CP) cells with wild-type p53, bcl-2 levels were markedly reduced. U2-OS/Pt cells had a 16-fold increase in the level of Bcl-xL protein. Stable transfection of U2-OS cells with bcl-xL cDNA conferred a low level of drug resistance to cisplatin, suggesting that overexpression of this gene contributes to the cisplatin-resistant phenotype of this osteosarcoma cell system. In conclusion, these observations suggest a variable contribution of apoptosis-related genes to cisplatin resistance depending on the biological background of the cell system and presumably reflecting different pathways of apoptosis.
authors.affiliation: Division of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. perego@istitutotumori.mi.it
authors.forename: P
authors.initials: P
authors.lastname: Perego
authors.forename: S C
authors.initials: SC
authors.lastname: Righetti
authors.forename: R
authors.initials: R
authors.lastname: Supino
authors.forename: D
authors.initials: D
authors.lastname: Delia
authors.forename: C
authors.initials: C
authors.lastname: Caserini
authors.forename: N
authors.initials: N
authors.lastname: Carenini
authors.forename: B
authors.initials: B
authors.lastname: Bedogné
authors.forename: E
authors.initials: E
authors.lastname: Broome
authors.forename: S
authors.initials: S
authors.lastname: Krajewski
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
authors.forename: F
authors.initials: F
authors.lastname: Zunino