Laboratory of Internal Medicine, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
Leuk Lymphoma. 2010 Jul;51(7):1337-46. doi: 10.3109/10428194.2010.488708.
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 (Deltapsim) 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 Deltapsim, 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.
多发性骨髓瘤（MM）是一种血液恶性肿瘤，其特征是老年人骨髓中克隆性浆细胞的不受控制增殖。尽管在 MM 的治疗方面已经取得了巨大进展，但它仍然是一种无法治愈的疾病。苦参碱是传统中药苦参的主要生物碱之一，已被证明可抑制多种癌细胞的细胞增殖并诱导细胞凋亡。本研究旨在探讨苦参碱作为 MM 患者新型治疗剂的可能性。我们研究了苦参碱在体外的抗骨髓瘤活性，并进一步研究了苦参碱诱导细胞凋亡的机制。苦参碱以剂量和时间依赖性方式抑制人骨髓瘤细胞系以及从患者中分离的新鲜骨髓瘤细胞的增殖。苦参碱对骨髓瘤细胞具有很强的诱导凋亡作用。线粒体膜电位（Deltapsim）丢失，细胞色素 c（cyt c）从线粒体释放到细胞质中，这是剂量依赖性的。苦参碱处理骨髓瘤细胞 48 小时后，Bcl-2/Bax 蛋白的比值降低，激活的 caspase-3 的百分比增加，但这种苦参碱诱导的 caspase-3 活性被 caspase-3 抑制剂 Z-Asp（O-Me）-Glu（O-Me）-Val-Asp（O-Me）氟甲基酮（Z-DEVD-FMK）的加入完全取消。Z-DEVD-FMK 的加入部分阻断了苦参碱对骨髓瘤细胞的凋亡作用。这些数据表明，苦参碱可以对骨髓瘤细胞发挥抗增殖作用，并在体外诱导骨髓瘤细胞凋亡。凋亡的诱导似乎通过线粒体途径进行，包括下调 Bcl-2/Bax 比值、Deltapsim 丢失、cyt c 从线粒体释放到细胞质、以及 caspase-3 的激活。这些发现支持苦参碱可能是一种有用的 MM 化疗药物候选物的观点。
