Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation.
OBJECTIVE
Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation.


RESULTS
Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC(50) of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts, and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release.


METHODS
We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases.


CONCLUSIONS
Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases.
Araujo
John C
JC
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. johna@mdanderson.org
Poblenz
Ann
A
Corn
Paul
P
Parikh
Nila U
NU
Starbuck
Michael W
MW
Thompson
Jerry T
JT
Lee
Francis
F
Logothetis
Christopher J
CJ
Darnay
Bryant G
BG
D000230:Adenocarcinoma / Q000556:secondary*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D001859:Bone Neoplasms / Q000556:secondary*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D000069439:Dasatinib; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D013844:Thiazoles; C505689:Tnfsf11 protein, mouse; D003094:Collagen; D019061:src-Family Kinases; D000069439:Dasatinib