Bisphosphonate induces apoptosis and inhibits pro-osteoclastic gene expression in prostate cancer cells.
OBJECTIVE
Bisphosphonates are well established for the management of cancer-induced skeletal complications. Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To determine the direct effects of bisphosphonate on prostate cancer, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis-related proteins and osteoclastogenic factors.


METHODS
PC-3, DU145 and LNCaP cells were treated with amino-bisphosphonate minodronate. Then proliferation, apoptosis and expression of bcl-2, bax, poly (ADP)-ribose polymerase (PARP), caspase-3, receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinases-2 (MMP-2), and parathyroid hormone related protein (PTHrP) were assessed.


RESULTS
The proliferation of prostatic cancer cells was inhibited by minodronate. DNA fragmentation and TUNEL-positive nuclei were observed in minodronate-treated PC-3 cells. Minodronate decreased bcl-2 expression and induced bax expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells.


CONCLUSIONS
Our results suggest that bisphosphonate not only promotes apoptosis directly but also decreases pro-osteoclastic gene expression in prostate cancer cells.
Asahi
Hideki
H
Department of Urology, School of Medicine, Kanazawa University, Kanazawa, Japan.
Mizokami
Atsushi
A
Miwa
Sotaro
S
Keller
Evan T
ET
Koshida
Kiyoshi
K
Namiki
Mikio
M
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics; D004164:Diphosphonates / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D016207:Cytokines; D004164:Diphosphonates; D006133:Growth Substances; D019253:Proto-Oncogene Proteins c-bcl-2; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3