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Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity
C M Shipman1, M J Rogers, J F Apperley
1Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School.
Abstract:
Bisphosphonates are in widespread use to prevent bone resorption in a number of metabolic and tumour-induced bone diseases including multiple myeloma. Recent reports suggest that bisphosphonate treatment may be associated with an increase in patient survival, raising the possibility that these compounds may have a direct effect on the tumour cells. We have investigated whether the bisphosphonates clodronate, pamidronate and YM175 can directly affect the human myeloma cell lines U266-B1, JJN-3 and HS-Sultan in vitro. The effect of bisphosphonate treatment on cell number and cell cycle progression was examined using flow cytometry. The ability of bisphosphonates to induce apoptosis in human myeloma cell lines was determined on the basis of changes in nuclear morphology and of DNA fragmentation. Pamidronate and the more potent bisphosphonate. YM175, significantly decreased cell number (P < 0.001) in JJN-3 and HS-Sultan cells. YM175 also caused cells to arrest in the S-phase of the cell cycle in the JJN-3 cell line. Both pamidronate and YM175 also caused an increase in the proportion of cells with altered nuclear morphology (P < 0.05) and fragmented DNA, characteristic of apoptosis, in both JJN-3 and HS-Sultan cells. In contrast, clodronate had little effect on cell number and did not cause apoptosis at the concentrations examined. These data raise the possibility that some bisphosphonates could have direct anti-tumour effects on human myeloma cells in vivo.
Insights
Certain bisphosphonates, like pamidronate and YM175, directly reduce human myeloma cell numbers and induce apoptosis in vitro. These findings suggest potential direct anti-myeloma effects for some bisphosphonates.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Bisphosphonates are standard treatments for bone resorption in diseases like multiple myeloma.
- Emerging evidence suggests bisphosphonates may improve patient survival, hinting at direct anti-tumour activity.
Purpose of the Study:
- To investigate the direct effects of bisphosphonates (clodronate, pamidronate, YM175) on human myeloma cell lines in vitro.
- To determine if these bisphosphonates can inhibit myeloma cell proliferation and induce apoptosis.
Main Methods:
- Human myeloma cell lines (U266-B1, JJN-3, HS-Sultan) were treated with bisphosphonates.
- Cell number and cell cycle progression were analyzed using flow cytometry.
- Apoptosis was assessed by examining nuclear morphology and DNA fragmentation.
Main Results:
- Pamidronate and YM175 significantly reduced cell numbers in JJN-3 and HS-Sultan lines (P < 0.001).
- YM175 induced S-phase cell cycle arrest in JJN-3 cells.
- Both pamidronate and YM175 increased markers of apoptosis (altered nuclear morphology, DNA fragmentation) in JJN-3 and HS-Sultan cells (P < 0.05).
- Clodronate showed minimal effects on cell number and apoptosis at tested concentrations.
Conclusions:
- Pamidronate and YM175 demonstrate direct anti-proliferative and pro-apoptotic effects on human myeloma cell lines in vitro.
- These findings suggest that certain bisphosphonates may possess direct anti-tumour activity against multiple myeloma.
- Further in vivo studies are warranted to explore the therapeutic potential of these bisphosphonates in multiple myeloma treatment.