Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling

Abstract

Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phospho-Src-Y416 (p-Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V-fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of p-Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p-Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated anti-ovarian cancer properties, by downregulating p-Src expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25-0.93 and 0.31-0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated anti-ovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian cancer cells appeared to be mediated by the Src pathway.