PDF(Pubmed)
Abstract：
Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.
摘要：
尽管随着化疗药物的发展,白血病的长期生存率取得了显著的进步,患者仍在复发，导致不满意的结果。发现新的有效抗白血病化合物,我们合成了一系列二苯胺并嘧啶，并通过使用白血病细胞系（HEL，Jurkat,和K562）。结果表明，二苯胺嘧啶类似物H-120在HEL细胞中主要表现出最高的细胞毒性潜力。它通过激活凋亡相关蛋白（裂解的caspase-3，裂解的caspase-9和裂解的聚ADP-核糖聚合酶（PARP））显着诱导HEL细胞凋亡，增加凋亡蛋白Bad的表达，降低抗凋亡蛋白(Bcl-2和Bcl-xL)的表达。此外，它诱导细胞周期阻滞在G2/M；同时，我们观察到p53的激活和磷酸化细胞分裂周期25C（p-CDC25C）/CyclinB1水平的降低。此外,机制研究表明，H-120降低了这些磷酸化的信号转导和转录激活因子3，大鼠肉瘤，磷酸化细胞RAF原癌基因丝氨酸/苏氨酸激酶，磷酸化丝裂原活化蛋白激酶激酶,磷酸化细胞外信号调节激酶，和细胞粒细胞瘤癌基因(p-STAT3，Ras，p-C-Raf,p-MEK,p-MRK,和c-Myc）HEL细胞中的蛋白质水平。使用细胞质和核蛋白分离试验，我们首次发现H-120可以抑制STAT3和c-Myc的激活，并阻断STAT3的磷酸化和二聚化。此外，H-120治疗通过促进红细胞向红细胞的成熟和激活免疫细胞，有效抑制红白血病小鼠的疾病进展。重要的是,H-120还改善了红白血病小鼠的肝功能。因此,H-120可能是白血病患者潜在的化疗药物。
