Bisphosphonates are potent inhibitors of osteoclast function widely used to treat excessive
bone resorption associated, e.g., with bone
metastases. They have also antitumor activity. However, it is unclear whether this reflects an indirect effect via inhibition of
bone resorption or a direct antitumor effect.
Nitrogen-containing
bisphosphonates (N-BPs), including
zoledronic acid (ZOL), act by inhibiting
farnesyl pyrophosphate synthase (FPPS). The
mevalonate pathway is blocked and the accumulation of
isopentenyl pyrophosphate (
IPP) consequently occurs.
IPP is conjugated to
AMP to form a novel
ATP analog (ApppI). The present study was undertaken to clarify whether
IPP and/or ApppI has a direct involvement in apoptosis caused by ZOL in different
cancer cell lines. There are marked differences in ZOL-induced ApppI formation between different
cancer cell lines. On this basis, we selected three
cancer cell lines that differ significantly from each other in their ZOL-induced
IPP and ApppI accumulation: human
estrogen-dependent (MCF7) and
estrogen-independent (MDA-MB 436)
breast cancer cell lines and a human myeloma cell line (RPMI 8226). The amount of
IPP/ApppI correlated with the capacity of cells to undergo apoptosis.
Geranylgeraniol (GGOH), an intermediate of
mevalonate metabolism, blocks both
IPP and ApppI formation and to some degree ZOL-induced apoptosis in a cell line-dependent manner. In addition,
lovastatin (LOV), an inhibitor of the
enzyme HMGCoA
reductase, completely blocks
IPP/ApppI formation as determined by mass spectrometry analysis, but enhances apoptosis. In conclusion, the current data suggest that ZOL-induced
IPP/ApppI formation can contribute to ZOL-induced apoptosis. This mechanism and the inhibition of protein prenylation, both outcomes of FPPS inhibition in
mevalonate pathway, seem to act in concert in ZOL-induced apoptosis in
cancer cells.