Src, a nonreceptor
tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid
tumors, including ovarian
carcinoma. The purpose of this study was to determine the role of activated Src inhibition on
tumor growth in an orthotopic murine model of ovarian
carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor,
AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of
docetaxel in both chemosensitive and chemoresistant
ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of
AP23846, significantly decreased
tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on
tumor reduction was observed in combination
therapy with
docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively).
Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with
docetaxel (P = 0.007) significantly reduced
tumor proliferation. In addition, Src inhibition alone and in combination with
docetaxel significantly down-regulated tumoral production of
vascular endothelial growth factor and
interleukin 8, whereas combination
therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces
tumor burden in preclinical
ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian
carcinoma.