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The level of ATP analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro
- Source :
- Bone. 45:1153-1160
- Publication Year :
- 2009
- Publisher :
- Elsevier BV, 2009.
-
Abstract
- 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.
- Subjects :
- Histology
Physiology
Endocrinology, Diabetes and Metabolism
Cell
Farnesyl pyrophosphate
Isopentenyl pyrophosphate
Apoptosis
Zoledronic Acid
chemistry.chemical_compound
Adenosine Triphosphate
Hemiterpenes
Organophosphorus Compounds
Geranylgeraniol
Cell Line, Tumor
Neoplasms
medicine
Humans
Lovastatin
Membrane Potential, Mitochondrial
Diphosphonates
Imidazoles
medicine.anatomical_structure
chemistry
Biochemistry
Drug Resistance, Neoplasm
Cancer cell
Cancer research
Protein prenylation
Mevalonate pathway
Diterpenes
Subjects
Details
- ISSN :
- 87563282
- Volume :
- 45
- Database :
- OpenAIRE
- Journal :
- Bone
- Accession number :
- edsair.doi.dedup.....f832e850500d92daa2005728ed0ef305