Modulation of sensitivity of human ovarian cancer cells to cis‐diamminedichloroplatinum(II) by 12‐O‐tetradecanoylphorbol‐13‐acetate and D, L‐buthionine‐S, R‐sulphoximine

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Abstract
The ability of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) and D, L‐buthionine‐S, R‐sulphoximine (BSO) to modulate cisdiamminedichloroplatinum(11) (CDDP) sensitivity was investigated in human ovarian cancer cell lines sensitive (KF) or with intrinsic resistance (KK and MH) to CDDP. The KK and MH cell lines were derived from ascites of patients with clear‐cell carcinoma and serous cystadenocarcinoma of the ovary who both showed clinical resistance to CDDP. The CDDP IC50 value of KK and MH cells was about 4.6‐ and 10.2‐fold higher than that of KF cells. PKC activities in the cytosol and membrane of KK and MH cells were also about 4‐ to 5‐fold higher than those of KF cells. Proliferation of KF, KK and MH cells was inhibited in a dose‐dependent manner by TPA. The membrane PKC activities in the KF cells were rapidly activated and down‐regulated 24 hr after exposure to TPA, while those in the KK and MH cells were not down‐regulated even after exposure to TPA for 24 hr, suggesting that the membrane form of PKC may be involved in the intrinsic resistance. Continuous exposure to 10 nM TPA for 5 days significantly reduced the CDDP sensitivity of KF and KK cells, while exposure to 10 nM TPA for I hr significantly elevated that of KK and MH cells. Interestingly, I ‐hr exposure to I m̈M TPA induced CDDP‐resistance in KK cells. Such changes in CDDP sensitivity by TPA seemed to be linked with those of cellular PKC activity, i.e., when the CDDP sensitivity was reduced by TPA, the cellular PKC rose. When the CDDP sensitivity was increased, the cellular PKC decreased. In addition, glutathione (GSH) levels in KK and MH cells, whose proliferation was more markedly inhibited by BSO than the KF‐cell proliferation, were about 7.6‐ and 1.9‐fold higher than those in KF cells. The degree of depletion of GSH by BSO was more marked in the KK and MH cells than in the KF cells, subsequently resulting in a significant elevation of the CDDP sensitivity of KK and MH (but not KF) cells. Our results suggest that intrinsic resistance to CDDP can be reduced by TPA or BSO under some conditions.