Multiple myeloma (MM) is a clonal B-cell malignancy characterized by slow-growing plasma cells in the bone marrow (BM).Patients with MM typically respond to initial chemotherapies; however, essentially all progress to a chemoresistant state. Factors that contribute to the chemorefractory phenotype include modulation of free radical scavenging, increased expression of drug efflux pumps, and changes in gene expression that allow escape from apoptotic signaling. Recent data indicate that arsenic trioxide (As 2 O 3 ) induces remission of refractory acute promyelocytic leukemia and apoptosis of cell lines overexpressing Bcl-2 family members; therefore, it was hypothesized that chemorefractory MM cells would be sensitive to As 2 O 3 . As 2 O 3 induced apoptosis in 4 human MM cell lines: 8226/S, 8226/Dox40, U266, and U266/Bcl-x L . The addition of interleukin-6 had no effect on cell death. Glutathione (GSH) has been implicated as an inhibitor of As 2 O 3 -induced cell death either through conjugating As 2 O 3 or by sequestering reactive oxygen induced by As 2 O 3 . Consistent with this possibility, increasing GSH levels with N-acetylcysteine attenuated As 2 O 3 cytotoxicity. Decreases in GSH have been associated with ascorbic acid (AA) metabolism. Clinically relevant doses of AA decreased GSH levels and potentiated As 2 O 3 -mediated cell death of all 4 MM cell lines. Similar results were obtained in freshly isolated human MM cells. In contrast, normal BM cells displayed little sensitivity to As 2 O 3 alone or in combination with AA. Together, these data suggest that As 2 O 3 and AA may be effective antineoplastic agents in refractory MM and that AA might be a useful adjuvant in GSH-sensitive therapies. IntroductionMultiple myeloma (MM) is an incurable B-cell malignancy characterized by infiltrating, slow-growing plasma cells in the bone marrow (BM) that produce monoclonal immunoglobulin molecules (reviewed in Hallek et al 1 ). MM accounts for 1% of all cancers and slightly more than 10% of all hematologic cancers, making it more common than Hodgkin disease and acute leukemia. 2 Current therapies for MM include alkylating agents (melphalan) and steroids (prednisone, dexamethasone) alone or combined with other antineoplastic agents, including plant alkaloids (vincristine, vinblastine) and anthracyclines (Adriamycin). 2 High-dose chemotherapy with autologous or allogeneic stem cell transplantation has resulted in some improvement in survival rates, 2 and a number of newer therapeutics are under investigation, including thalidomide. 3 However, MM has an invariably aggressive course; essentially all (more than 90%) patients progress to a chemoresistant or refractory state. Even with treatment, the median 5-year survival rate for patients with MM is less than 25%. 2 Thus, it is clear that new therapeutics are needed for the treatment of refractory MM.At least 4 distinct mechanisms contribute to the acquisition of the chemoresistant phenotype in MM that must be overcome or circumvented to effectively treat refractory disea...

The Bcl-2 family of proteins are key regulators of apoptosis. Bcl-xL, is an anti-apoptotic protein with a high degree of homology to Bcl-2; however, the signals that regulate Bcl-xL and Bcl-2 appear to be different. Levels of Bcl-xL, but not Bcl-2, are increased in response to various survival signals. Furthermore, an inverse correlation between the levels of Bcl-2 and Bcl-xL has been reported for a number of cancers. Although the precise molecules that control Bcl-xL activity are unclear, the STAT, Rel/NF-kappaB, and Ets transcription factor families have recently been reported to directly regulate the bcl-x gene. Activated Ras, integrin, vitronectin, and hepatocyte growth factor signaling cascades have also been linked to changes in Bcl-xL expression. Bcl-xL can also be affected by post-translational mechanisms. Here we review recent advances in identifying the signaling pathways and factors involved in regulation of the bcl-x gene.