Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2

Arsenic trioxide (ATO) is a well-known inhibitor of cell proliferation. Preclinical and clinical studies showed that ATO has anti-myeloma effects. However, the underlying mechanism remains elusive. In this study, the molecular mechanisms of ATO-induced myeloma apoptosis were explored on four myeloma cell lines of wild-type or mutant p53 status and also on six primary myeloma cells. ATO induced potent inhibition of myeloma cell growth and myeloma cell apoptosis compared with controls. Further investigation showed that ATO downregulated c-Myc and phosphorylated (p)-Rb while upregulating p53, p21Cip1 and p27Kip1 proteins, resulting in G0/G1 or G2/M cell cycle arrest. ATO treatment increased mRNA levels of interferon regulatory factor-1 and TRAIL, as well as protein levels of caspase 8 and cleaved caspase 3, indicating the involvement of the extrinsic apoptotic pathway in the mutated p53 myeloma cells. ATO also activated caspases 3 and 9, indicating involvement of the intrinsic apoptotic pathway in the wild type p53 myeloma cells. More importantly, these molecular changes induced by ATO-treated myeloma cells are very similar to the baseline expression pattern of hyperdiploid myeloma, which has a relative good prognosis with high expression of TRAIL and interferon related genes. Together, our data suggest that ATO induces apoptosis in multiple myeloma through either extrinsic or intrinsic signaling pathway, depending on the p53 genetic background. These observations may be employed as prognostic tools and lead to novel therapies in primary myelomas.