Effect Of Arsenic Trioxide On The Bone Marrow Stromal Cells Of Multiple Myeloma

Objective The bone marrow stromal cells(BMSCs) plays a crucial role in the pathogenesis of multiple myeloma(MM).The paracrine and autocrine production of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) contribute to the growth and drug-resistance of MM cells. This study is to explore the effect of arsenic trioxide (As₂O₃) on growth and secretion of VEGF and IL-6 of BMSCs from the multiple myeloma patients, and to provide a rationale for its clinical trials in treatment of relapsed and refractory MM.Methods Specimens of bone marrow aspiration form MM patients were used to establish BMSCs cultures. BMSCs and CZ-1 were cultured together or alone in the presence or absence of As₂O₃ at various concentration(1¹0μM). Cell growth inhibition was assessed by MTT assay; cytokines in the culture supernatants was measured with ELISA.Results As₂O₃ showed cytostatic effect on CZ-1 with fifty percent growth inhibition (IC₅0) for 48h at 2.3μM. Growth of BMSCs was not inhibited by As₂O₃ There was no significance difference between the control and BMSCstreated with relative high concentration (20uM) of As2O3 at 48h(P=0.45). High levels of IL-6 and VEGF have been found in the culture supernatants of BMSCs from MM. Secretion of IL-6 from CZ-1 was not detected. The secretion of IL-6 and VEGF were increased in the group of BMSCs cultured with CZ-1, which was much higher than they were cultured alone. Cytokine production of BMSCs treated with AS2O3 was significantly decreased as compared with controls (PO.05). Excitingly, even the increased cytokine production triggered by adhesion of MM cell and BMSCs was also inhibited by As2O3.Conclusion Arsenic trioxide inhibited the growth of MM cell in a dose dependent manner. There was no cytostatic effect on BMSCs. Arsenic trioxide inhibited the production of IL-6 and VEGF by BMSCs, and also blocked the elevated secretion of cytokines induced by the binding of MM cell to BMSCs.