Zoledronic Acid Inhibits Cell Growth of Multiple Myeloma Cells and Shows Synergistic Antimyeloma Effects with Bortezomib Via CD38 /cADPR /Ca2+ /Ras /Pakt /NF-Kb /Pim-2 Pathway

The Third-generation biphosphonate Zoledronic acid (ZOL) can exhibit direct antitumour activity which is widely used in multiple myeloma (MM) patients with bone events. However,it remains unknown whether Zol alone or combined with Bortezomib(B) has any inhibitory effect on myeloma cells. In this study, cell line RPMI-8226 were treated with ZOL alone at various concentrations and combined with Bortezomib to observe the effect and probable molecular mechanisms.Cell proliferation,cell apoptosis,cell phenotype(CD38+ and CD138+),RT-PCR, measurement of intracellular [Ca2+] concentration and Western blot analyses were performed.We found that ZOL alone strongly inhibited proliferation of multiple myeloma cells in vitro, and induced their apoptosis.The same results were obtained in the myeloma cell group treated with ZOL combined with Bortezomib after 24h instead of 48h.On the mechanism study, we found that Zol alone or combined with Bortezomib in 24h suppressed the mean fluorescence intensity(MFI) of CD38 and the mRNA of cADPR,NF-Kb,pim-2 ,and the signal pathway protein Ras/pAkt/NF-Kb/pim-2 and the intracellular [Ca2+]i concentration.However, it did not show the same results in 48h. In conclusion, Zol inhibited cell growth of multiple myeloma cells probably via suppressing CD38/cADPR/Ca2+/Ras/pAkt/NF-Kb/pim-2 pathway.Combination of Zol with Bortezomib within 24 hours maybe more benefitial to alleviate tumour load in MM patients.