Enhancement of Antiproliferative Effect of cis-Diamminedichloroplatinum (II) by Clomiphene and Tamoxifen in Human Ovarian Cancer Cells

Abstract

In this study, we examined antiproliferative effect of clomiphene and tamoxifen alone and their combined effect on cis -diamminedichloroplatinum(II) (CDDP) by using human ovarian cancer cells (KF, KK, and MH cells) with different sensitivity to CDDP and MCF-7 cells derived from human breast cancer. KF, KK, and MH cells did not have estrogen receptor while MCF-7 cells had it. The KF cells were most sensitive to CDDP followed by KK, MCF-7, and MH cells. Similarly, the KF cells among three human ovarian cancer cell lines were most sensitive to clomiphene and tamoxifen alone. The MCF-7 cells had similar high sensitivity to both clomiphene and tamoxifen. When effects of clomiphene and tamoxifen on the protein kinase C (PKC) activity in the cancer cells were examined, the degree of inhibition of the PKC activity in the KF cells by clomiphene and tamoxifen was most marked and that by clomiphene was followed by those by KK, MH, and MCF-7 cells, while that by tamoxifen was, in increasing order, MH, MCF-7, and KK cells. Analyses of effects of clomiphene or tamoxifen on concentrations of CDDP required for 50% inhibition of cell proliferation (IC50) revealed that although the combined effects, in the KF and KK cells were only marginal, marked enhancement of antiproliferative effects of CDDP on the MH cells resistant to CDDP was obtained. When 5 × 106 cells were incubated with 100 μM CDDP for 3 hr, uptake of CDDP by MCF-7 cells was lowest, followed by MH, KK, and KF cells. The CDDP uptake by KF and KK cells was increased about 30-40% in the presence of clomiphene or tamoxifen. The CDDP uptake by the MH cells in which most marked enhancement of antiproliferative effect of CDDP was observed by a combination with clomiphene or tamoxifen was increased about 80-90% in the presence of clomiphene or tamoxifen. These results suggest that not only tamoxifen but also clomiphene can potentiate antiproliferative effect of CDDP in the ER-negative CDDP-resistant cancer cells by enhancing the CDDP uptake.