Mechanisms of the action of zoledronic acid on human MG-63 osteosarcoma cells.
The aim of our study was to analyze the action of zoledronic acid on MG-63 human osteosarcoma cells. The proliferation of MG-63 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner (10-250 microM). Zoledronic acid did not produce evidence of MG-63 cell death when administered at 100 mM for 48 hours, but only after exposure of 96 hours. Zoledronic acid (100 microM) increased the distribution of MG-63 cells in G0/G1 phase, however, it did not increase the adriamycin-induced apoptosis. In addition, zoledronic acid action was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), but not by farnesyl pyrophosphate (FPP). Furthermore, zoledronic acid resulted in the attenuation of the prenylated form of Ras. Zoledronic acid and EDTA increased fluorescence of Fluo-3 loaded MG-63 cells in a similar pattern. This increase was owing to the release of Ca2+ from intracellular stores since zoledronic acid failed to reveal such a change to intracellular Ca2+ when cells were previously treated with 1 mM caffeine. Moreover, zoledronic acid significantly decreased the expression of estrogen receptor alpha (ERalpha) whereas it did not change significantly the expression of estrogen receptor beta (ERbeta) in MG-63 cells. These data suggest that zoledronic acid can control the proliferation and the differentiation of osteosarcoma-like cells.
Department of Experimental Physiology, Medical School, University of Athens, Goudi-Athens Greece.
R
R
Tenta
N
N
Pitulis
D
D
Tiblalexi
C
C
Consoulas
H
H
Katopodis
E
E
Konstantinidou
M
M
Manoussakis
D
D
Kletsas
M N
MN
Alexis
A
A
Poyatzi
M
M
Koutsilieris
D000814:Aniline Compounds; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004492:Edetic Acid / Q000494:pharmacology; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012516:Osteosarcoma / Q000737:chemistry / Q000473:pathology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000032:analysis; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D014966:Xanthenes; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000032:analysis
D000814:Aniline Compounds; D004164:Diphosphonates; D005456:Fluorescent Dyes; D007093:Imidazoles; D011106:Polyisoprenyl Phosphates; D011960:Receptors, Estrogen; D012717:Sesquiterpenes; D014966:Xanthenes; C059715:Fluo-3; D000077211:Zoledronic Acid; C004808:farnesyl pyrophosphate; D004317:Doxorubicin; D004492:Edetic Acid; D018631:ras Proteins; C002963:geranylgeranyl pyrophosphate; D002118:Calcium