P-glycoprotein expression in ovarian cancer cell line following treatment with cisplatin.

Human ovarian cancer cell line SKOV3 was grown during a period of four months in the presence of increasing concentrations of cisplatin (25-100 ng/ml). In the course of this treatment, the cells exhibited dramatic changes in morphology, including reduction in cell size, loss of cellular projections and clustering. This was accompanied by the appearance of P-glycoprotein (Pgp) on the cell membrane, as detected by flow cytometry and immunochemistry methods using the anti-Pgp monoclonal antibodies MRK16 and C219. The new cell line, designated SKOV3/CIS, was also resistant to alkylating agents, such as chlorambucil, similarly to the parental SKOV3 cells. In addition, it also acquired resistance to classical multidrug resistance drugs, such as doxorubicin, taxol and actinomycin D. Verapamil enhanced the sensitivity of SKOV3/CIS to doxorubicin (260-fold), in conformity with the proposed mechanism of Pgp in multidrug resistance (MDR), but it did not potentiate cisplatin cytotoxicity in SKOV3/CIS cells. Our results suggest that cisplatin can cause Pgp expression, and that both cisplatin-resistance and Pgp-mediated MDR phenotypes can coexist in some tumor types. Although Pgp does not appear to be responsible for cisplatin resistance, exposure to cisplatin can lead to the development of MDR phenotype, a complication that should be considered in clinical situations, especially in the chemotherapy of ovarian cancer.