Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells
Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells
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DOI：
10.1158/1535-7163.mct-08-0664
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发表时间：
2009-02-01
影响因子：
5.7
通讯作者：
Schmidmaier, Ralf
中科院分区：
文献类型：
--
作者：
Baumann, Philipp;Mandl-Weber, Sonja;Schmidmaier, Ralf
多发性骨髓瘤仍然是一种无法治愈的疾病;因此，迫切需要新的治疗方法。A771726是免疫抑制药物来氟米特的活性代谢产物，目前应用于治疗类风湿性关节炎、BK病毒肾病和巨细胞病毒血症。在这里，我们表明，二氢乳清酸脱氢酶（DHODH）通常在多发性骨髓瘤细胞系和原发性多发性骨髓瘤细胞中表达。DHODH抑制剂A771726在临床可达到的浓度下以时间和剂量依赖性方式抑制常见骨髓瘤细胞系中的细胞生长。Annexin V-FITC/碘化丙啶染色显示诱导多发性骨髓瘤细胞系和原代多发性骨髓瘤细胞凋亡。5-溴-2 '-脱氧尿苷细胞增殖试验表明，细胞生长的抑制部分是由于多发性骨髓瘤细胞增殖的抑制。A771726通过调节cyclin D2和pRb的表达诱导G1细胞周期阻滞。蛋白质印迹实验显示，A771726降低蛋白激酶B（Akt）、p70 S6 K和真核翻译起始因子4 E结合蛋白-1的磷酸化。此外，我们发现HS-5骨髓基质细胞条件培养基对多发性骨髓瘤细胞生长的刺激作用完全被A771726消除。此外，协同作用研究显示A771726与遗传毒性剂美法仑、曲奥舒凡和多柔比星以及地塞米松和硼替佐米具有协同和相加活性。总之，我们表明A771726/来氟米特对DHODH的抑制在多发性骨髓瘤中是有效的。考虑到来氟米特在类风湿关节炎中良好的毒性特征和丰富的临床经验，这种药物代表了多发性骨髓瘤靶向治疗的潜在新候选药物。[Mol癌症治疗2009;8（2）：366-75]
Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time- and dose-dependent manner. Annexin V-FITC/propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2'-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G, cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma. [Mol Cancer Ther 2009;8(2):366-75]