The bisphosphonate YM529 inhibits osteolytic and osteoblastic changes and CXCR-4-induced invasion in prostate cancer.
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.
Miwa
Sotaro
S
Department of Urology, Kanazawa University, Kanazawa, Japan.
Mizokami
Atsushi
A
Keller
Evan T
ET
Taichman
Russell
R
Zhang
Jian
J
Namiki
Mikio
M
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000473:pathology* / Q000517:prevention & control* / Q000556:secondary; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010006:Osteoblasts / Q000187:drug effects* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D004164:Diphosphonates; D007093:Imidazoles; D019718:Receptors, CXCR4; C087958:YM 529