The nonreceptor
tyrosine kinase c-Src is frequently over-expressed or hyperactivated in various human
cancers and contributes to
cancer progression in cooperation with up-regulated
growth factor receptors. However, Src-selective anticancer drugs are still in clinical trials. To identify more effective inhibitors of c-Src-mediated
cancer progression, we developed a new screening platform using Csk-deficient cells that can be transformed by c-Src. We found that
purvalanol A, developed as a CDK inhibitor, potently suppressed the anchorage-independent growth of c-Src-transformed cells, indicating that the activation of CDKs contributes to the c-Src transformation. We also found that
purvalanol A suppressed the c-Src activity as effectively as the Src-selective inhibitor PP2, and that it reverted the transformed morphology to a nearly normal shape with less cytotoxicity than PP2.
Purvalanol A induced a strong G2-M arrest, whereas PP2 weakly acted on the G1-S transition. Furthermore, when compared with PP2,
purvalanol A more effectively suppressed the growth of human
colon cancer HT29 and SW480 cells, in which
Src family kinases and CDKs are activated. These findings demonstrate that the coordinated inhibition of cell cycle progression and
tyrosine kinase signaling by the multi-selective
purvalanol A is effective in suppressing
cancer progression associated with c-Src up-regulation.