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Role of apoptosis and apoptosis-related proteins in the cisplatin-resistant phenotype of human tumor cell lines

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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 ci splatin-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.

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Authors and Affiliations

  1. Divisions of Experimental Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

    P. Perego, S. C. Righetti, R. Supino, C. Caserini, N. Carenini, B. Bedogné & F. Zunino

  2. Experimental Oncology A, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

    D. Delia

  3. University of California, San Diego, USA

    E. Broome

  4. The Burhnam Institute, La Jolla, USA

    S. Krajewski & J. C. Reed

Authors
  1. P. Perego
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  2. S. C. Righetti
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  3. R. Supino
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  4. D. Delia
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  5. C. Caserini
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  6. N. Carenini
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  7. B. Bedogné
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  8. E. Broome
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  9. S. Krajewski
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  10. J. C. Reed
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Perego, P., Righetti, S.C., Supino, R. et al. Role of apoptosis and apoptosis-related proteins in the cisplatin-resistant phenotype of human tumor cell lines. Apoptosis 2, 540–548 (1997). https://doi.org/10.1023/A:1026442716000

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  • DOI: https://doi.org/10.1023/A:1026442716000

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