TY - JOUR
T1 - Dasatinib inhibits both osteoclast activation and prostate cancer PC-3 cell-induced osteoclast formation
AU - Araujo, John C.
AU - Poblenz, Ann
AU - Corn, Paul
AU - Parikh, Nila U.
AU - Starbuck, Michael W.
AU - Thompson, Jerry T.
AU - Lee, Francis
AU - Logothetis, Christopher J.
AU - Darnay, Bryant G.
PY - 2009/11/15
Y1 - 2009/11/15
N2 - Purpose: 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. Experimental design: 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. Conclusion: Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cellinduced 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.
AB - Purpose: 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. Experimental design: 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. Conclusion: Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cellinduced 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.
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U2 - 10.4161/cbt.8.22.9770
DO - 10.4161/cbt.8.22.9770
M3 - Article
C2 - 19855158
AN - SCOPUS:77951496674
SN - 1538-4047
VL - 8
SP - 2153
EP - 2159
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 22
ER -