Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines andin plasma cells from myeloma patients

Recent data have renewed the interest for arsenic-containing compounds as a nticancer agents. In particular, arsenic trioxide (As2O3) has been demonstr ated to be an effective drug in the treatment of acute promyelocytic leukem ia by inducing programmed cell death in leukemic cells both in vitro and in vivo. This prompted us to study the in vitro effects of As2O3 and of anoth er arsenical derivative, the organic compound melarsoprol, on human myeloma cells and on the plasma cell differentiation of normal B cells. At pharmacological concentrations (10(-8) to 10(-6) mol/L), As2O3 and melar soprol caused a dose- and time-dependent inhibition of survival and growth in myeloma cell lines that was, in some, similar to that of acute promyeloc ytic leukemia cells. Both arsenical compounds induced plasma cell apoptosis , as assessed by 4',6-diamidino-2-phenylindole staining, detection of phosp hatidylserine at the cell surface using annexin V, and by the terminal deox ynucleotidyl transferase-mediated nick end labeling assay. As2O3 and melars oprol also inhibited viability and growth and induced apoptosis in plasma-c ell enriched preparations from the bone marrow or blood of myeloma patients . In nonseparated bone marrow samples, both arsenical compounds triggered d eath in myeloma cells while sparing most myeloid cells, as demonstrated by double staining with annexin V and CD38 or CD15 antibodies. In primary myel oma cells as in cell lines, interleukin 6 did not prevent arsenic-induced c ell death or growth inhibition, and no synergistic effect was observed with IFN-alpha. In contrast to As2O3, melarsoprol only slightly reduced the plasma cell dif ferentiation of normal B cells induced by pokeweed mitogen, Both pokeweed m itogen-induced normal plasma cells and malignant plasma cells showed a norm al nuclear distribution of PML protein, which was disrupted by As2O3 but no t by melarsoprol, suggesting that the two arsenical derivatives acted by di fferent mechanisms. These results point to the use of arsenical derivatives as investigational drugs in the treatment of multiple myeloma.