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.
Footnotes
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↵1 Supported by USPHS Grant PO1-CA-47179. J. R. B. is an American Cancer Society Professor of Medicine and Pharmacology.
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↵2 To whom requests for reprints should be addressed, at present address: Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08093. Phone: (732) 235-8510; Fax: (732) 235-8181; E-mail: bertinoj{at}umdnj.edu
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↵3 The abbreviations used are: STS, soft tissue sarcoma; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; MTX, methotrexate; DOX, doxorubicin; DAPI, 4′6-diamidino-2-phenylindole; PMSF, phenylmethylsulfonyl fluoride; FACS, fluorescence-activated cell sorter; SRB, sulforhodamine B.
- Accepted October 11, 2002.
- Received December 11, 2001.
- Revision received July 12, 2002.
- Molecular Cancer Therapeutics
Volume 1, Issue 14
