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Department of Cell Biology, Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, District of Columbia

Requests for reprints: Christopher C. Taylor, Department of Cell Biology, Vincent T. Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, D.C. 20007. Phone: 202-687-2552; Fax: 202-687-1823. E-mail: cct5{at}georgetown.edu

Src tyrosine kinase has been found to be overexpressed and activated in a high proportion of ovarian cancers and ovarian cancer cell lines. Furthermore, Src activation is associated with activation of growth and survival signaling pathways. The present study was conducted in order to determine the effects of Src inhibition on ovarian cancer cell survival in response to chemotherapeutic agents. Inhibition of Src, either pharmacologically or through expression of a Src dominant-negative fusion construct, enhanced the cytotoxicity of two different classes of chemotherapeutics: paclitaxel and cisplatinum, in both mouse and human ovarian cancer cells. Interestingly, Src inhibition also restored sensitivity to drug-resistant ovarian cancer cells. The increased cytotoxicity in response to Src inhibition was associated with a large increase in processing and activation of caspase-3. The activation of caspase-3 seems to be independent of cytochrome c release and caspase-9 activation. The present study indicates that Src tyrosine kinase may provide an important target for small molecule inhibition in ovarian cancer.

Key Words: Src • caspase-3 • ovarian cancer

Grant support: Department of Defense grant OC990038 (C.C. Taylor). We also thank Alex Potocki and the Department of Cell Biology Confocal Microscopy Core Facility, the Tissue Culture and Flow Cytometry Shared Resources of Lombardi Cancer Center, which are partially supported by NIH Grant 1P30-CA-51008 (Cancer Center Support Grant to Lombardi Cancer Center).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/17/04; revised 12/ 3/04; accepted 12/ 9/04.