Abstract
Sensitivity of human soft tissue sarcoma (STS) cells to methotrexate, doxorubicin, and paclitaxel was examined after cells were pretreated with CH-11, an agonistic anti-Fas antibody. A subtoxic dose (6 ng/ml) of CH-11 sensitized STS cells but not normal fibroblast cells to these anticancer drugs. CH-11 increased cytochrome c release and consequent activation of caspase-9, independent of caspase-8 and increased p38 activation. Addition of SB203580, a specific inhibitor of p38, resulted in a decrease in activation of this kinase and abrogation of enhanced chemosensitivity (doxorubicin and paclitaxel) by CH-11. These results demonstrate that stimulation of the Fas pathway by a subtoxic dose of a Fas agonist can selectively enhance sensitivity of STS cells to certain chemotherapeutic agents through activation of p38.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents, Phytogenic / pharmacology
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Blotting, Western
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Caspase 9
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Caspases / metabolism
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Cell Cycle
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Cell Death
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Cell Separation
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Chalcone / analogs & derivatives*
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Chalcone / pharmacology
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Chalcones
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Cytochrome c Group / metabolism
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology
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Enzyme Activation
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Flow Cytometry
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Humans
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Imidazoles / pharmacology
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Mitogen-Activated Protein Kinases / metabolism*
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Paclitaxel / pharmacology
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Pyridines / pharmacology
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Sarcoma / metabolism*
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Sarcoma / pathology*
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Signal Transduction*
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Soft Tissue Neoplasms / metabolism*
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Soft Tissue Neoplasms / pathology*
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Time Factors
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Tumor Cells, Cultured
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fas Receptor / metabolism*
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p38 Mitogen-Activated Protein Kinases
Substances
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4-dimethylamino-3',4'-dimethoxychalcone
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Antibiotics, Antineoplastic
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Antineoplastic Agents
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Antineoplastic Agents, Phytogenic
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Chalcones
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Cytochrome c Group
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Imidazoles
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Pyridines
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fas Receptor
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Chalcone
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Doxorubicin
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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CASP9 protein, human
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Caspase 9
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Caspases
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SB 203580
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Paclitaxel