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Acquisition of chemoresistance in a human ovarian carcinoma cell line is linked to a defect in cell cycle control
Author(s) -
Poulain Laurent,
Lincet Hubert,
Duigou Françoise,
Deslandes Edwige,
Sichel François,
Gauduchon Pascal,
Staedel Cathy
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19981109)78:4<454::aid-ijc11>3.0.co;2-6
Subject(s) - cisplatin , apoptosis , cell cycle , cancer research , biology , ovarian cancer , cell cycle checkpoint , ovarian carcinoma , cell culture , carboplatin , cancer , chemotherapy , genetics
Chemoresistance is a major concern in cancer erradication; it involves various mechanisms, including defects in the apoptosis program induced by anticancer drugs. In order to further explore the mechanisms underlying the development of chemoresistance in ovarian carcinoma after cisplatin treatment, we established an in vitro model, mimicking a clinical protocol of administration of cisplatin. Therefore, IGROV1 ovarian carcinoma cells were exposed for 2 hr to the drug and allowed to recover for several weeks; this way of exposure was reiterated with escalating doses. We followed changes in cytotoxicity of the drug, cell cycle kinetics and long‐term survival of cells after cisplatin treatment, and found that resistance to cisplatin was not associated with altered apoptosis pathway, since both cisplatin sensitive and resistant cells underwent apoptosis in a similar way. Acquisition of resistance to cisplatin was associated with the ability of the treated cells to progress through the cell cycle beyond the G 1 /S checkpoint; although most cells died by apoptosis, a few surviving cells proliferated and recolonized the cultures. Compared to sensitive cells, the chemoresistant variants were able to override the G 1 /S checkpoint whatever the dose, and the recurrent cells recolonized the cultures much faster. Analysis of alterations in gene expression suggests that the defect in cell cycle regulation could take place at the level of the cdk inhibitor p21 CIP1/WAF1 . Int. J. Cancer 78:454–463, 1998. © 1998 Wiley‐Liss, Inc.