Safa Majid, Jafari Leila, Alikarami Fatemeh, Manafi Shabestari Rima, Kazemi Ahmad
1 Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
2 Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
Tumour Biol. 2017 Jun;39(6):1010428317705768. doi: 10.1177/1010428317705768.
Signal transducer and activator of transcription 5 and Akt pathways, implicated in signaling transduction downstream of BCR-ABL, play critical roles in the pathogenesis of chronic myeloid leukemia. Therefore, idenication of novel compounds that modulate the activity of such pathways could be a new approach in the treatment of chronic myeloid leukemia. Previous studies have demonstrated that indole-3-carbinol inhibits the proliferation and induces apoptosis of various tumor cells. However, its anticancer activity against chronic myeloid leukemia cells and the underlying mechanism remain unclear. Our data revealed that indole-3-carbinol promoted mitochondrial apoptosis of chronic myeloid leukemia-derived K562 cells, as evidenced by the activation of caspases and poly (ADP-ribose) polymerase cleavage. Treatment with indole-3-carbinol was found to be associated with a decrease in the cellular levels of phospho-Akt and phospho-signal transducer and activator of transcription 5. In addition, real-time polymerase chain reaction analysis showed that the downregulation of genes is regulated by Akt and signal transducer and activator of transcription 5. We also found that treatment with indole-3-carbinol resulted in the activation of the p38 mitogen-activated protein kinase and reduced expression of human telomerase and c-Myc. Collectively, these results demonstrate that the oncogenic signal transducer and activator of transcription 5/Akt pathway is a cellular target for indole-3-carbinol in chronic myeloid leukemia cells. Thus, this clinically tested natural compound can be a potential candidate in the treatment of chronic myeloid leukemia following confirmation with clinical studies.
信号转导及转录激活因子5和Akt信号通路参与BCR-ABL下游的信号转导，在慢性髓性白血病的发病机制中起关键作用。因此，鉴定调节此类信号通路活性的新型化合物可能是治疗慢性髓性白血病的一种新方法。先前的研究表明，吲哚-3-甲醇可抑制多种肿瘤细胞的增殖并诱导其凋亡。然而，其对慢性髓性白血病细胞的抗癌活性及其潜在机制仍不清楚。我们的数据显示，吲哚-3-甲醇可促进慢性髓性白血病来源的K562细胞发生线粒体凋亡，半胱天冬酶的激活和聚（ADP-核糖）聚合酶的切割证明了这一点。发现用吲哚-3-甲醇处理与磷酸化Akt和磷酸化信号转导及转录激活因子5的细胞水平降低有关。此外，实时聚合酶链反应分析表明，基因的下调受Akt以及信号转导及转录激活因子5的调控。我们还发现，用吲哚-3-甲醇处理可导致p38丝裂原活化蛋白激酶的激活以及人端粒酶和c-Myc表达的降低。总体而言，这些结果表明，致癌信号转导及转录激活因子5/Akt信号通路是吲哚-3-甲醇在慢性髓性白血病细胞中的细胞靶点。因此，这种经过临床测试的天然化合物经临床研究证实后，可能成为治疗慢性髓性白血病的潜在候选药物。
