Molecular characterization of c-Abl/c-Src kinase inhibitors targeted against murine tumour progenitor cells that express stem cell markers.

Background: The non-receptor tyrosine kinases c-Abl and c-Src are overexpressed in various solid human tumors. Inhibition of their hyperactivity represents a mol. rationale in the combat of cancerous diseases. Here we examd. the effects of a new family of pyrazolo [3,4-d] pyrimidines on a panel of 11 different murine lung tumor progenitor cell lines, that express stem cell markers, as well as on the human lung adenocarcinoma cell line A549, the human hepatoma cell line HepG2 and the human colon cancer cell line CaCo2 to obtain insight into the mode of action of these exptl. drugs. Methodol./Principal Findings: Treatment with the dual kinase inhibitors blocked c-Abl and c-Src kinase activity efficiently in the nanomolar range, induced apoptosis, reduced cell viability and caused cell cycle arrest predominantly at G0/G1 phase while western blot anal. confirmed repressed protein expression of c-Abl and c-Src as well as the interacting partners p38 mitogen activated protein kinase, heterogenous ribonucleoprotein K, cyclin dependent kinase 1 and further proteins that are crucial for tumor progression. Importantly, a significant repression of the epidermal growth factor receptor was obsd. while whole genome gene expression anal. evidenced regulation of many cell cycle regulated genes as well integrin and focal adhesion kinase (FAK) signalling to impact cytoskeleton dynamics, migration, invasion and metastasis. Conclusions/Significance: Our expts. and recently published in vivo engraftment studies with various tumor cell lines revealed the dual kinase inhibitors to be efficient in their antitumor activity.