Abstract
Cisplatin (CDDP) is a major chemotherapeutic drug used in the treatment of human ovarian cancer. Tubeimoside I (TBMS1) has also shown potent antitumor and antitumor-promoting effects, and may offer a promising new approach in the effective treatment of CDDP-resistant human ovarian cancers. This study aimed to investigate the effect of TBMS1 in sensitizing CDDP in CDDP-resistant human ovarian cancer cells (A2780/DDP). A variety of methods were employed to measure cell apoptosis, p38, ERK1/2 and glutathione S-transferase (GST)-π expressions. It was found that TBMS1 combined with CDDP promoted cell apoptosis, decreased proliferation activity and increased cytosolic Ca2+ levels. Bcl-2 protein expression was down-regulated but Bax was up-regulated. Moreover, GST-π mRNA and protein expression were decreased. TBMS1 reduced the resistance of the cells to CDDP-induced cytotoxicity. Both the p38 inhibitor (SB203580) and the ERK1/2 inhibitor (PD98059) effectively blocked this effect. These results suggest that TBMS1 can effectively sensitize CDDP in CDDP-resistant human ovarian cancer cells through the down-regulation of the ERK1/2 and the up-regulation of the p38 signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium / metabolism
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Cell Death / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cisplatin / pharmacology*
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Cisplatin / therapeutic use
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects*
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Drug Resistance, Neoplasm / drug effects*
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Drug Screening Assays, Antitumor
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Drug Synergism
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Glutathione S-Transferase pi / genetics
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Glutathione S-Transferase pi / metabolism
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Humans
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MAP Kinase Signaling System / drug effects*
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / enzymology*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / pathology
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Protein Kinase Inhibitors / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Saponins / pharmacology*
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Saponins / therapeutic use
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Triterpenes / pharmacology*
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Triterpenes / therapeutic use
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Up-Regulation / drug effects*
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bcl-2-Associated X Protein / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Protein Kinase Inhibitors
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RNA, Messenger
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Saponins
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Triterpenes
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bcl-2-Associated X Protein
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tubeimoside I
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Glutathione S-Transferase pi
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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Cisplatin
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Calcium