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The Bisphosphonate YM529 Inhibits Osteolytic and Osteoblastic Changes and CXCR-4–Induced Invasion in Prostate Cancer

¹ Department of Urology, Kanazawa University, Kanazawa, Japan and ² Department of Urology, School of Medicine, and ³ Department of Periodontics, Prevention and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Atsushi Mizokami, Department of Urology, Kanazawa University, 13-14 Takaramachi, Kanazawa-city, Japan 920-8640. Phone: 81-76-265-2393; Fax: 81-76-222-6726; E-mail: mizokami{at}med.kanazawa-u.ac.jp.

Bisphosphonates are useful for the treatment of prostate cancer bone metastasis. However, the role of bisphosphonate on the development of the osteoblastic component of prostate cancer bone metastases is not defined. In the present study, the third-generation bisphosphonate, YM529 (minodoronate), was tested for its effects on the osteolytic PC-3 and novel osteoblastic LNCaP-SF cell lines. YM529 inhibited both osteolytic and osteoblastic changes in an intratibial tumor injection murine model. In vitro, YM529 inhibited both the proliferation and the invasion of both prostate cancer cell lines. The stromal cell–derived factor-1 (or CXCL12)/CXCR-4 pathway is believed to play an important role in the development of prostate cancer bone metastases. Thus, we determined if YM529 affected this pathway. YM529 suppressed CXCR-4 expression in PC-3 and LNCaP-SF in vitro and in vivo and this was associated with decreased in vitro invasion. These results suggest that YM529 may inhibit cancer cell invasion into the bone matrix by repressing the expression of CXCR-4 in bone metastasis lesions.

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