title: Apomine, an inhibitor of HMG-CoA-reductase, promotes apoptosis of myeloma cells in vitro and is associated with a modulation of myeloma in vivo.
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 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.
authors.affiliation: Institute of Musculoskeletal Sciences and the Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Center, Oxford, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Edwards
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Mueller
authors.forename: Anke J
authors.initials: AJ
authors.lastname: Roelofs
authors.forename: Andrew
authors.initials: A
authors.lastname: Chantry
authors.forename: Mark
authors.initials: M
authors.lastname: Perry
authors.forename: R Graham G
authors.initials: RG
authors.lastname: Russell
authors.forename: Ben
authors.initials: B
authors.lastname: Van Camp
authors.forename: Yves
authors.initials: Y
authors.lastname: Guyon-Gellin
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Niesor
authors.forename: Craig L
authors.initials: CL
authors.lastname: Bentzen
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
mesh_terms: 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
chemical_list: D004164:Diphosphonates; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010266:Paraproteins; C407151:apomine