Matrine induces apoptosis of human multiple myeloma cells via activation of the mitochondrial pathway

Multiple myeloma (MM) is a hematological malignancy characterized by the uncontrolled proliferation of clonal plasma cells in bone marrow in the elderly. Although there have been tremendous advances in the treatment of MM, it remains an incurable disease. Matrine, a main alkaloid of the traditional Chinese herb Sophora flavescens Ait, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. The aim of this study was to investigate the possibility of matrine as a novel therapeutic agent for patients with MM. We investigated the effects of matrine for its anti-myeloma activity in vitro, and further examined the mechanisms of apoptosis induced by matrine. Matrine inhibited the proliferation of human myeloma cell lines as well as freshly isolated myeloma cells from patients in a dose- and time-dependent manner. Matrine showed a potent induction of apoptosis of myeloma cells. Mitochondrial membrane potential (Delta psi m) was lost and cytochrome c (cyt c) was released from mitochondria to cytosol in myeloma cells treated by matrine for 24 h in a dose- dependent manner. The ratio of Bcl-2/Bax protein decreased, and the percentage of activated caspase-3 increased in myeloma cells treated by matrine for 48 h, but this matrine-induced activity of caspase-3 was completely canceled by the addition of Z-Asp(O-Me)-Glu(O-Me)-Val-Asp(O-Me) fluoromethyl ketone (Z-DEVD-FMK), a caspase-3 inhibitor. The addition of Z-DEVD-FMK partially blocked the apoptotic effect of matrine on myeloma cells. These data indicated that matrine could exert antiproliferative effects on myeloma cells and induce apoptosis of myeloma cells in vitro. The induction of apoptosis appeared to proceed via the mitochondrial pathway, including down-regulation of Bcl-2/Bax ratio, loss of Delta psi m, release of cyt c from mitochondria to cytosol, and activation of caspase-3. These findings support the view that matrine may be a useful candidate as a chemotherapeutic agent against MM.