Abstract | OBJECTIVE: METHODS: We treated 7 ovarian cancer cell lines with CDDP alone or with CDDP and either a PI3K inhibitor ( LY294002), a MEK inhibitor ( PD98059), or a MEK/ERK activator ( phorbol 12- myristate 13- acetate [PMA]) and assessed cell viability, expression of MEK/ERK and PI3K/Akt, cell cycle distribution, and apoptosis. We also investigated the effect of combination treatment on survival in a xenograft model. RESULTS: The cell lines showed half-maximal inhibitory concentrations (IC50) of CDDP from 2.4 to 26.9 μmol/L. KFr, a CDDP-resistant cell line developed from KF cells, showed an IC50 of CDDP of 9.6 μmol/L. Five of the cell lines with IC50 values of 9.6 μmol/L or greater were defined as CDDP-resistant. Cisplatin and LY294002 had an additive effect on inhibiting cell growth, and CDDP and PD98059 had and antagonistic effect on cell growth in all cell lines. In CDDP-resistant cells, CDDP and PMA dramatically suppressed the cell growth, up-regulated the expression of phosphorylated ERK and cleaved caspase-9, down-regulated the expression of checkpoint kinases, and increased the proportion of cells in the synthesis-phase fraction and apoptotic cells. The treatment of nude mice with CDDP and PMA prolonged survival in an ovarian cancer xenograft model. CONCLUSIONS: The present study indicates that further study is warranted to determine the effectiveness of combination treatment with CDDP and PMA for platinum-resistant ovarian carcinoma.
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Authors | Michiko Nonaka, Hiroaki Itamochi, Wakae Kawaguchi, Akiko Kudoh, Seiya Sato, Kazunori Uegaki, Jun Naniwa, Shinya Sato, Muneaki Shimada, Tetsuro Oishi, Naoki Terakawa, Junzo Kigawa, Tasuku Harada |
Journal | International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
(Int J Gynecol Cancer)
Vol. 22
Issue 6
Pg. 922-9
(Jul 2012)
ISSN: 1525-1438 [Electronic] England |
PMID | 22672985
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Chromones
- Flavonoids
- Morpholines
- Phosphoinositide-3 Kinase Inhibitors
- 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
- phorbolol myristate acetate
- Mitogen-Activated Protein Kinase Kinases
- Tetradecanoylphorbol Acetate
- Cisplatin
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Topics |
- Adenocarcinoma
(drug therapy)
- Animals
- Antineoplastic Agents
(therapeutic use)
- Cell Death
(drug effects)
- Cell Line, Tumor
- Chromones
(pharmacology, therapeutic use)
- Cisplatin
(therapeutic use)
- Drug Resistance, Neoplasm
(drug effects)
- Drug Synergism
- Female
- Flavonoids
(pharmacology, therapeutic use)
- Humans
- MAP Kinase Signaling System
(drug effects)
- Mice
- Mice, Nude
- Mitogen-Activated Protein Kinase Kinases
(antagonists & inhibitors)
- Morpholines
(pharmacology, therapeutic use)
- Ovarian Neoplasms
(drug therapy)
- Phosphoinositide-3 Kinase Inhibitors
- S Phase
(drug effects)
- Tetradecanoylphorbol Acetate
(analogs & derivatives, pharmacology, therapeutic use)
- Xenograft Model Antitumor Assays
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