Effect of the specific Src family kinase inhibitor saracatinib on osteolytic lesions using the PC-3 bone model.
The hematogenous metastatic spread of prostate cancer is preferentially to bone and can result in significant patient morbidity. Although these metastatic lesions are typically osteoblastic, bone resorption is believed to have a prerequisite role in their development. Src kinase has been identified to contribute to prostate cancer tumor growth and metastasis. In addition, Src is also essential in bone metabolism, especially in bone resorption. We hypothesized that inhibiting Src activity with the specific Src family kinase inhibitor saracatinib (AZD0530) would inhibit tumor cell growth and osteoclast differentiation in the tumor-bone interface, thus providing a new approach for advanced prostate cancer. We found that saracatinib inhibited PC-3 cell growth and invasion in a dose-dependent manner. Phosphorylation of Src, focal adhesion kinase, and P38 kinases was inhibited by saracatinib at the submicromolar range. Saracatinib also inhibited the expression and secretion of invasion-related molecules interlukin-8, urokinase-type plasminogen activator, and matrix metalloprotease-9. Receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis and signaling were inhibited by saracatinib in both macrophages and PC-3 cells. In in vivo studies, control mice developed more severe osteolytic lesions compared with the treatment group. Immunohistochemical and biochemical assays of bone metabolites confirmed that saracatinib preserved bone architecture in the presence of prostate cancer tumor cells. In summary, we have shown the inhibition of PC3 cell growth and invasion by saracatinib. Src inhibition also blocked the RANKL stimulatory pathway in osteoclasts and PC3 cells. The inhibition of Src thus targets multiple sites involved in prostate cancer bone metastasis, which may offer a therapeutic advantage in treating advanced prostate cancer.
Yang
Joy C
JC
Department of Urology, University of California at Davis, Sacramento, California 95817, USA.
Bai
Lanfang
L
Yap
Stanley
S
Gao
Allen C
AC
Kung
Hsing-Jien
HJ
Evans
Christopher P
CP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D053245:RANK Ligand / Q000494:pharmacology; D011859:Radiography; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D052117:Benzodioxoles; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D053245:RANK Ligand; C515233:saracatinib; D019061:src-Family Kinases