Apomine, an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo.
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 bisphosphonate, alendronate, had no measurable effect on osteoclastic bone resorption in vitro. To investigate the effect of Apomine in vivo, 5T2MM murine 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.
Edwards
Claire M
CM
Institute of Musculoskeletal Sciences and the Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Center, Oxford, United Kingdom.
Mueller
Gabrielle
G
Roelofs
Anke J
AJ
Chantry
Andrew
A
Perry
Mark
M
Russell
R Graham G
RG
Van Camp
Ben
B
Guyon-Gellin
Yves
Y
Niesor
Eric J
EJ
Bentzen
Craig L
CL
Vanderkerken
Karin
K
Croucher
Peter I
PI
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010266:Paraproteins / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010266:Paraproteins; C407151:apomine