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.
The ability of 12-O-tetradecanoylphorbol-13-acetate (TPA) and D,L-buthionine-S,R-sulphoximine (BSO) to modulate cis-diamminedichloroplatinum(II) (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 1 hr significantly elevated that of KK and MH cells. Interestingly, 1-hr exposure to 1 microM 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Hirata
J
J
Department of Obstetrics and Gynecology, National Defense Medical College, Saitama, Japan.
Kikuchi
Y
Y
Kita
T
T
Imaizumi
E
E
Tode
T
T
Ishii
K
K
Kudoh
K
K
Nagata
I
I
D019328:Buthionine Sulfoximine; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003536:Cystadenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D002945:Cisplatin