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Vol. 54, Issue 4, 631-638, October 1998
Department of Medicine and Therapeutics, University of Aberdeen
Medical School, Foresterhill, Aberdeen, AB25 2ZD, UK (F.P.C., H.L.B.,
M.J.R.), and
Department of Human Metabolism and Clinical Biochemistry,
University of Sheffield Medical School, Sheffield S10 2RX, UK (F.P.C.,
R.G.G.R.)
The exact mechanisms of action of antiresorptive bisphosphonate drugs
remain unclear, although they may inhibit bone resorption by mechanisms
that can lead to osteoclast apoptosis. These drugs also cause apoptosis
in J774 macrophages, probably as a consequence of inhibition of protein
prenylation. However, the molecular pathways that lead to apoptosis are
not known. In some cells, apoptosis induced by statins (other
inhibitors of protein prenylation) is dependent on protein synthesis.
The aim of this study was to further characterize the kinetics and
biochemical features of bisphosphonate-induced apoptosis, including the
dependence on protein synthesis. Alendronate-induced apoptosis in J774
cells occurred after ~16 hr of treatment, although shorter exposures
to the drug followed by incubation in bisphosphonate-free medium also
committed cells to apoptosis. The appearance of apoptotic cells was
associated with the appearance of caspase-3-like activity. Apoptosis
induced by bisphosphonate or mevastatin was found to be dependent on
protein synthesis because cycloheximide inhibited chromatin
condensation, DNA fragmentation and activation of caspase-3-like protease or proteases. Protein synthesis was required for events that
lead to commitment to apoptosis but not for the execution phase because
cycloheximide did not prevent apoptosis when added 
15 hr after the
start of alendronate treatment. Furthermore, staurosporine-induced
caspase-3-like activity and apoptosis in J774 cells could not be
prevented by cycloheximide. These observations demonstrate that
activation of caspase-3-like proteases and inhibition of commitment to
apoptosis by cycloheximide are common features of apoptotic cell death
induced by inhibitors of protein prenylation such as bisphosphonates.
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