Arsenic trioxide induces multiple myeloma cell apoptosis via disruption ofmitochondrial transmembrane potentials and activation of caspase-3

Objective To investigate the response of multiple myeloma (MM) cells to ars enic trioxide (As2O3) and their possible mechanisms. Methods Two MM-derived cell lines RPMI8226 and U266 cells were used as in v itro models. Cell apoptosis was assessed by morphology, flow cytometry, and DNA gel electrophoresis. Mitochondrial transmembrane potentials (Delta Psi m) were evaluated by measuring cellular Rhodamine 123 staining intensity. P rotein expression was analyzed using Western blot. Results Zero point one to 0.5 mu mol/l As2O3 inhibited cell proliferation a nd 2.0 mu mol/L As2O3 induced cell apoptosis, while 1.0 mu mol/l As2O3 inhi bited proliferation with a weak degree of apoptosis induction in RPMI8226 a nd U266 cell lines. As2O3-induced apoptosis was accompanied by mitochondria l transmembrane potentials (Delta Psim) collapse and caspase-3 activation i n the presence of intact membrane. Glutathione depleter buthionine sulfoxim ine enhanced, while disulfide bond-reducing agent dithiothreitol partially antagonized As2O3-induced Delta Psim collapse and apoptosis in MM cells. Al l-trans retinoic acid (ATRA) could also induce apoptosis in RPMI8226 cells, but it did not show any cooperative effects with As2O3. Conclusion As2O3 exerts apoptosis-inducing and growth-inhibiting effects on MM cells, and mitochondrium is a pivotal and common target of As2O3 for ap optosis induction.