Uchihara Yuki, Tago Kenji, Funakoshi-Tago Megumi
Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University.
Division of Structural Biochemistry, Department of Biochemistry, Jichi Medical University.
Nihon Yakurigaku Zasshi. 2019;153(4):147-154. doi: 10.1254/fpj.153.147.
Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are caused by a fusion protein, BCR-ABL, which induces cellular transformation by activating the signaling molecules, STAT5 and Akt. The specific BCR-ABL inhibitors including imatinib, nilotinib, and dasatinib, are clinically utilized in the treatment with CML and ALL patients. Although these BCR-ABL inhibitors are initially successful in the treatment of leukemia, many patients develop drug resistance due to the appearance of the gatekeeper mutation of BCR-ABL, T315I. Recently, we found that taxodione, a quinone methide diterpene isolated from a conifer, Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which is positive for the bcr-abl gene. Taxodione reduced the activities of mitochondrial respiratory chain complex III, leading to the production of reactive oxygen species (ROS). An antioxidant agent, N-acetylcysteine (NAC), canceled taxodione-induced ROS production and apoptotic cell death, suggesting that taxodione induced apoptosis through ROS accumulation. Furthermore, in K562 cells treated with taxodione, BCR-ABL, STAT5 and Akt were sequestered in mitochondrial fraction, and their localization changes decrease their abilities to stimulate cell proliferation. Strikingly, NAC canceled these taxodione-caused inhibition of BCR-ABL, STAT5 and Akt. In addition, taxodione significantly induced apoptosis in transformed Ba/F3 cells by not only BCR-ABL but also T315I-mutated BCR-ABL through the generation of ROS, suggesting that taxodione has potential as anti-tumor drug with high efficacy to overcome BCR-ABL T315I mutation-mediated resistance in leukemia cells. It's also expected that these knowledge becomes an important clue in the development of anti-cancer drugs against the broad range of tumors.
慢性粒细胞白血病（CML）和急性淋巴细胞白血病（ALL）是由一种融合蛋白BCR-ABL引起的，该蛋白通过激活信号分子STAT5和Akt诱导细胞转化。包括伊马替尼、尼洛替尼和达沙替尼在内的特异性BCR-ABL抑制剂在临床上用于治疗CML和ALL患者。尽管这些BCR-ABL抑制剂最初在白血病治疗中取得了成功，但许多患者由于BCR-ABL的守门基因突变T315I的出现而产生耐药性。最近，我们发现从针叶树落羽杉中分离出的一种醌甲基二萜类化合物紫杉二酮，能显著诱导人骨髓性白血病来源的K562细胞凋亡，该细胞bcr-abl基因呈阳性。紫杉二酮降低了线粒体呼吸链复合体III 的活性，导致活性氧（ROS）的产生。抗氧化剂N-乙酰半胱氨酸（NAC）消除了紫杉二酮诱导的ROS产生和凋亡性细胞死亡，表明紫杉二酮通过ROS积累诱导凋亡。此外，在用紫杉二酮处理的K562细胞中，BCR-ABL、STAT5和Akt被隔离在线粒体部分，它们的定位变化降低了它们刺激细胞增殖的能力。令人惊讶的是，NAC消除了这些紫杉二酮对BCR-ABL、STAT5和Akt的抑制作用。此外，紫杉二酮通过产生ROS，不仅显著诱导了由BCR-ABL而且由T315I突变的BCR-ABL转化 的Ba/F3细胞凋亡，这表明紫杉二酮有潜力成为一种高效的抗肿瘤药物，以克服白血病细胞中BCR-ABL T315I突变介导的耐药性。人们还期望这些知识成为开发针对广泛肿瘤的抗癌药物的重要线索。
