Apomine (TM), an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo

Claire M. Edwards, Gabrielle Mueller, Anke J. Roelofs, Andrew Chantry, Mark Perry, R. Graham G. Russell, Ben Van Camp, Yves Guyon-Gellin, Eric J. Niesor, Craig L. Bentzen, Karin Vanderkerken, Peter I. Croucher

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphospbonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM marine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease. (c) 2007 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)1657-1663
Number of pages7
JournalInternational Journal of Cancer
Volume120
Issue number8
Early online date17 Jan 2007
DOIs
Publication statusPublished - 15 Apr 2007

Keywords

  • multiple myeloma
  • apomine
  • apoptosis
  • osteoclast
  • HMG-CoA reductase
  • farnesyl transferase inhibitor
  • nitrogen-containing bisphosphonates
  • multiple-myeloma
  • bone-resorption
  • tumor-cells
  • protein geranylgeranylation
  • diphosphate synthase
  • mevalonate pathway
  • disease

Cite this

Apomine (TM), an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo. / Edwards, Claire M.; Mueller, Gabrielle; Roelofs, Anke J.; Chantry, Andrew; Perry, Mark; Russell, R. Graham G.; Van Camp, Ben; Guyon-Gellin, Yves; Niesor, Eric J.; Bentzen, Craig L.; Vanderkerken, Karin; Croucher, Peter I.

In: International Journal of Cancer, Vol. 120, No. 8, 15.04.2007, p. 1657-1663.

Research output: Contribution to journalArticle

Edwards, CM, Mueller, G, Roelofs, AJ, Chantry, A, Perry, M, Russell, RGG, Van Camp, B, Guyon-Gellin, Y, Niesor, EJ, Bentzen, CL, Vanderkerken, K & Croucher, PI 2007, 'Apomine (TM), an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo', International Journal of Cancer, vol. 120, no. 8, pp. 1657-1663. https://doi.org/10.1002/ijc.22478
Edwards, Claire M. ; Mueller, Gabrielle ; Roelofs, Anke J. ; Chantry, Andrew ; Perry, Mark ; Russell, R. Graham G. ; Van Camp, Ben ; Guyon-Gellin, Yves ; Niesor, Eric J. ; Bentzen, Craig L. ; Vanderkerken, Karin ; Croucher, Peter I. / Apomine (TM), an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo. In: International Journal of Cancer. 2007 ; Vol. 120, No. 8. pp. 1657-1663.
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abstract = "Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphospbonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM marine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease. (c) 2007 Wiley-Liss, Inc.",
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T1 - Apomine (TM), an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo

AU - Edwards, Claire M.

AU - Mueller, Gabrielle

AU - Roelofs, Anke J.

AU - Chantry, Andrew

AU - Perry, Mark

AU - Russell, R. Graham G.

AU - Van Camp, Ben

AU - Guyon-Gellin, Yves

AU - Niesor, Eric J.

AU - Bentzen, Craig L.

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AU - Croucher, Peter I.

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N2 - Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphospbonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM marine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease. (c) 2007 Wiley-Liss, Inc.

AB - Apomine, a novel 1,1 bisphosphonate ester, increases the rate of degradation of HMG-CoA reductase, inhibiting the mevalonate pathway and thereby blocking cholesterol biosynthesis. We have investigated whether Apomine can induce myeloma cell apoptosis in vitro and modulate myeloma disease in vivo. Apomine induced a dose-dependent increase in apoptosis in NCI H929, RPMI 8226 and JJN-3 human myeloma cells. Apomine, unlike the bisphospbonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM marine myeloma cells were injected into C57BL/KaLwRij mice. After 8 weeks all animals had a serum paraprotein and were treated with Apomine (200 mg/kg), or vehicle, for 4 weeks. Animals injected with 5T2MM cells and treated with vehicle developed osteolytic bone lesions, reduced cancellous bone area, decreased bone mineral density (BMD) and increased osteoclast number. Apomine caused a decrease in serum paraprotein and a decrease in tumor burden. Apomine inhibited the development of osteolytic lesions and prevented the tumor-induced decreases in BMD. Apomine had no effect on osteoclast number in contrast to what had been seen previously with the bisphosphonate, zoledronic acid, suggesting that these are direct effects of Apomine on myeloma cells. This demonstrates that Apomine is able to promote myeloma cell apoptosis in vitro and inhibit the development of multiple myeloma and lytic bone disease in vivo. The use of bisphosphonate esters such as Apomine represents a novel therapeutic approach in the treatment of myeloma and, indirectly, the associated bone disease. (c) 2007 Wiley-Liss, Inc.

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KW - apomine

KW - apoptosis

KW - osteoclast

KW - HMG-CoA reductase

KW - farnesyl transferase inhibitor

KW - nitrogen-containing bisphosphonates

KW - multiple-myeloma

KW - bone-resorption

KW - tumor-cells

KW - protein geranylgeranylation

KW - diphosphate synthase

KW - mevalonate pathway

KW - disease

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DO - 10.1002/ijc.22478

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JO - International Journal of Cancer

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