Sato Masanori, Sagawa Morihiko, Nakazato Tomonori, Ikeda Yasuo, Kizaki Masahiro
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Int J Oncol. 2007 Jun;30(6):1453-9.
Several anti-cancer agents are derivative from natural products and microorganisms. The dolastatins are natural peptides derived from the marine mollusc Dolabella auricularia, which have recently been reported as an anti-cancer agent. Dolastatin 10 and 15 are small peptides; most preclinical studies have used dolastatin 10. It has been reported that dolastatins have cytotoxic activity by inhibiting microtubule assembly, and several clinical studies have already begun for solid tumors. However, the effects of dolastatin 15 against hematological malignancies such as myeloma cells have never been reported. We demonstrate here for the first time that dolastatin 15 induces cell cycle arrest at the G2/M phase followed by apoptosis in various human myeloma cell lines (RPMI8226, U266, and IM9), suggesting that it has effects on mitotic spindles. In addition, we showed that dolastatin 15 induces apoptosis of myeloma cells via activation of both mitochondrial- and Fas (CD95)/Fas-L (CD95-L)-mediated pathways. Our investigations have identified a novel inhibitor of microtubule assembly that induces mitotic arrest and apoptosis of myeloma cells. Therefore, it is possible that dolastatin 15 might be a novel and safe therapeutic agent for patients with multiple myeloma.
几种抗癌药物是天然产物和微生物的衍生物。多拉司他汀是从海洋软体动物耳状珊瑚中提取的天然肽，最近被报道为一种抗癌药物。多拉司他汀10和15是小肽；大多数临床前研究使用的是多拉司他汀10。据报道，多拉司他汀通过抑制微管组装具有细胞毒性活性，并且已经针对实体瘤开展了多项临床研究。然而，多拉司他汀15对血液系统恶性肿瘤如骨髓瘤细胞的作用从未被报道过。我们在此首次证明，多拉司他汀15在各种人骨髓瘤细胞系（RPMI8226、U266和IM9）中诱导细胞周期停滞在G2/M期，随后发生凋亡，这表明它对有丝分裂纺锤体有影响。此外，我们表明多拉司他汀15通过激活线粒体和Fas（CD95）/Fas-L（CD95-L）介导的途径诱导骨髓瘤细胞凋亡。我们的研究确定了一种新型的微管组装抑制剂，它能诱导骨髓瘤细胞的有丝分裂停滞和凋亡。因此，多拉司他汀15有可能成为一种新型且安全的治疗多发性骨髓瘤患者的药物。
