New Src Kinase Inhibitors Fb2 Anti-prostate Cancer Effects And Mechanisms

SFK (Src family kinase, SFK) belong to non-receptor tyrosine kniase. As the first discovered onprotein. Src plays a critical role in variety of cellular signal transduction pathways, regulating such diverse processes as cell division, motility, adhesion, invasion, survival and as so on. Also, elevated expression levels and activity of Src kinase have been observed in various human cancer cells and tumor tissues. Thus, Src kinase has been viewed as a significant target for cancer therapy and Src kinase inhibitors potentially provide new approaches toward cancer treatment. This study is aimed to evaluate the antitumor activity and its mechanisms of FB2. a novel Src kinase inhibitor, on prostate cancer.In vitro, FB2 significantly inhibited the proliferations of cancer cells derived from various tissue origins, including human prostate cancer cells DU145 and PC-3, human lung adenocarcinoma cells A549, human ovary adenocarcinoma cancer cells SK-OV-3, human melanoma cells A-375 and human breast adenocarcinoma cells MDA-MB-231. The results of MTT assay showed that IC₅₀ of FB2 toward these tumor cells were between 17nM and 73nM after treatment for 72h. In SRB assays, FB2 markedly suppressed the growth of DU145 and PC-3 cells and the GI50 toward the two prosate cancer cells were 14.3nM and 7.1nM respectively after treatment for 72h. And FB2 signifieantly blocked colony formation in DU145 and PC-3 cells at 1nM. In vivo, FB2 administered by ig inhibited growth of PC-3 xenograft in nude mice. FB2 administered at 18, 36, 72mg/kg/day caused a 45.5%, 51.4% and 59.4% inhibition, in tumor weight of PC-3 xenograft at the end of the animal experiment respectively.The mechanisms of FB2 against prostate cancer were also studied. Flow cytometry analysis showed that FB2 caused DU145 and PC-3 cells arrest at G₁ phase in dose-dependent manner; it also decreased the cell-cell contact in DU145 cells; pretreated with FB2 for 30min DU145 and PC-3 cells adhesion to Matrigel were markedly blocked; in the wound-healing assays, DU145 cell migration was inhibited by FB2; Zymography gelatin showed that FB2 caused a decrease of secretions of MMP-2 and MMP-9 from HT-1080, MMP-1 from DU145 cells.Besides, in western blot assay, after treatment with FB2 1μM for 30min, the levesl of p-Src (Y416) in DU-145 and PC-3 cells were markedly decreased and the levels of Src protein were not impacted at all. The results of Western blot and immunohistochemistry analysis on PC-3 xenograft tumors showed that FB2, administrated by ig at 72mg/kg, decreased the levels of p-Src (Y416) in vivo.Thus, FB2, a novel Src kinase inhibitor, had potent antitumor activity in vitro and in vivo, presented a potentially useful therapeutic compound for cancer therapy. Its mechanisms were related to decreased level of tyrosine phosphorylation of Src at Y416.