Wang Yuping, Chen Jie, Wang Lin, Huang Yuji, Leng Ye, Wang Guiying
Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092; ; Department of Biochemistry, School of Medicine, Jinggangshan University, Jiangxi 343009;
Exp Ther Med. 2013 Apr;5(4):1105-1112. doi: 10.3892/etm.2013.924. Epub 2013 Jan 24.
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease caused by the oncoprotein BCR-ABL, which exhibits a constitutive tyrosine kinase activity. Imatinib mesylate (IM), an inhibitor of the tyrosine kinase activity of BCR-ABL, has been used as a first-line therapy for CML. However, IM is less effective in the accelerated phase and blastic phases of CML and certain patients develop IM resistance due to the mutation and amplification of the BCR-ABL gene. Fangchinoline, an important chemical constituent from the dried roots of S. Moore, exhibits significant antitumor activity in various types of cancers, including breast, prostate and hepatocellular carcinoma. However, the effects and the underlying mechanisms of fangchinoline in CML remain unclear. In the present study, we identified that fangchinoline inhibits cell proliferation in a dose- and time-dependent manner in K562 cells derived from the blast crisis of CML. Additional experiments revealed that fangchinoline induces cell cycle arrest at the G0/G1 phase and has no effect on apoptosis, which is mediated through the upregulation of cyclin-dependent kinase (CDK)-N1A and MCL-1 mRNA levels, as well as the downregulation of cyclin D2 (CCND2) mRNA levels. These findings suggest the potential of fangchinoline as an effective antitumor agent in CML.
慢性粒细胞白血病（CML）是一种由癌蛋白BCR-ABL引起的造血干细胞疾病，该蛋白具有组成性酪氨酸激酶活性。甲磺酸伊马替尼（IM）是BCR-ABL酪氨酸激酶活性的抑制剂，已被用作CML的一线治疗药物。然而，IM在CML的加速期和急变期疗效较差，并且某些患者由于BCR-ABL基因的突变和扩增而产生IM耐药性。粉防己碱是青藤干燥根中的一种重要化学成分，在包括乳腺癌、前列腺癌和肝细胞癌在内的多种癌症中表现出显著的抗肿瘤活性。然而，粉防己碱在CML中的作用及其潜在机制仍不清楚。在本研究中，我们发现粉防己碱在源自CML急变期的K562细胞中以剂量和时间依赖性方式抑制细胞增殖。进一步的实验表明，粉防己碱诱导细胞周期停滞在G0/G1期，并且对凋亡没有影响，这是通过细胞周期蛋白依赖性激酶（CDK）-N1A和MCL-1 mRNA水平的上调以及细胞周期蛋白D2（CCND2）mRNA水平的下调介导的。这些发现表明粉防己碱作为CML有效抗肿瘤药物的潜力。
