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.