Bone microenvironment-related growth factors modulate differentially the anticancer actions of zoledronic acid and doxorubicin on PC-3 prostate cancer cells.
OBJECTIVE
We analyzed the actions of zoledronic acid (10-250 microM) and doxorubicin (10-250 nM) on PC-3 prostate cancer cells using both continuous (48-96 hr) and pulsatile exposures (15 min/day for up to three consecutive days).


RESULTS
The proliferation of PC-3 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner. In contrast, pulsatile exposures of doxorubicin failed to inhibit the growth of PC-3 cells. In addition, the inhibition of PC-3 cells by zoledronic acid was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), however, not by farnesyl pyrophosphate (FPP). Furthermore, exogenous administration of transforming growth factor beta 1 (TGF-beta1), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and more potently, insulin-like growth factor 1 (IGF-1) inhibited the doxorubicin-induced apoptosis of PC-3 cells. Under identical experimental conditions, these growth factors failed to alter the cytotoxicity of PC-3 cells induced by zoledronic acid.


CONCLUSIONS
These data suggest that (i) repetitive and pulsatile (15 min/day) exposure to zoledronic acid inhibited the growth of PC-3 cells, (ii) this anticancer action of zoledronic acid was partially mediated by the attenuation of GGPP production, and (iii) bone microenvironment-related growth factors do not alter the anticancer actions of zoledronic acid on PC-3 cells.
Tenta
Roxane
R
Department of Experimental Physiology, Medical School, University of Athens, Goudi-Athens, Greece.
Tiblalexi
Despina
D
Sotiriou
Evangelia
E
Lembessis
Peter
P
Manoussakis
Menelaos
M
Koutsilieris
Michael
M
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001842:Bone and Bones; D002455:Cell Division / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid
D000903:Antibiotics, Antineoplastic; D004164:Diphosphonates; D006133:Growth Substances; D007093:Imidazoles; D011106:Polyisoprenyl Phosphates; D000077211:Zoledronic Acid; D004317:Doxorubicin; C002963:geranylgeranyl pyrophosphate