Fas-mediated signaling enhances sensitivity of human soft tissue sarcoma cells to anticancer drugs by activation of p38 kinase

Mol Cancer Ther. 2002 Dec;1(14):1343-8.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Blotting, Western
  • Caspase 9
  • Caspases / metabolism
  • Cell Cycle
  • Cell Death
  • Cell Separation
  • Chalcone / analogs & derivatives*
  • Chalcone / pharmacology
  • Chalcones
  • Cytochrome c Group / metabolism
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology
  • Enzyme Activation
  • Flow Cytometry
  • Humans
  • Imidazoles / pharmacology
  • Mitogen-Activated Protein Kinases / metabolism*
  • Paclitaxel / pharmacology
  • Pyridines / pharmacology
  • Sarcoma / metabolism*
  • Sarcoma / pathology*
  • Signal Transduction*
  • Soft Tissue Neoplasms / metabolism*
  • Soft Tissue Neoplasms / pathology*
  • Time Factors
  • Tumor Cells, Cultured
  • fas Receptor / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • 4-dimethylamino-3',4'-dimethoxychalcone
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Chalcones
  • Cytochrome c Group
  • Imidazoles
  • Pyridines
  • fas Receptor
  • Chalcone
  • Doxorubicin
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • CASP9 protein, human
  • Caspase 9
  • Caspases
  • SB 203580
  • Paclitaxel