Inhibition of protein kinase c-Src as a therapeutic approach for cancer and bone metastases.
c-Src is a proto-oncogene involved in the genesis of and invasion by many cancers. This non-receptor tyrosine kinase also plays a crucial role in bone homeostasis, since inhibition or deletion of c-Src impairs the function of osteoclasts, the bone resorbing cells. It is thus conceivable that c-Src could be a suitable target for the pharmacological treatment of cancers, skeletal metastases and diseases of bone loss, such as osteoporosis. The pyrrolo-pyrimidines CGP77675 and CGP76030 proved to be effective in preventing bone loss in animal models, while the effect of AZD0530, a dually active inhibitor of c-Src and Bcr-ABL, on bone resorption, has been tested in a Phase I clinical trials with promising results. As far as the metastatic bone disease is concerned, c-Src inhibitors could potentially have inhibitory effects both on osteoclasts and on tumour cells, and could disrupt the vicious circle established between these cell types in the bone microenvironment. In accord with this idea, CGP76030 is able to reduce the incidence of osteolytic lesions and of visceral metastases, and to suppress morbidity and lethality in a bone metastasis mouse model without obvious adverse effects. The purine-based c-Src inhibitor AP23451 and the dual c-Src/Abl inhibitors AP22408 and AP23236 proved efficacious in reducing bone metastases in preclinical studies. These results open a new avenue for the development of innovative therapies for the treatment of bone metastatic disease.
Rucci
Nadia
N
Department of Experimental Medicine, University of L'Aquila, Via Vetoio - Coppito 2, 67100 L'Aquila, Italy.
Susa
Maria
M
Teti
Anna
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010010:Osteoclasts / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019061:src-Family Kinases