The mortality rates for acute myeloid leukemia are very high, necessitating the search for novel chemotherapeutic candidates. Herein, we investigated the anticancer potential of a new synthetic compound, 2-ethyl-3-methyliden-1-tosyl-2,3-dihydroquinolin-4-(1H)-one (AJ-374) against myeloid leukemia HL-60 cell line. This analog was selected from the small library of synthetic dihydroquinolinones on the basis of its strong antiproliferative activity against HL-60 cells and 30-fold lower cytotoxicity towards healthy HUVEC cells. AJ-374 promoted the arrest of the cells in the subG0/G1 phase of the cell cycle in the first 24 h. Treatment of HL-60 cells with AJ-374 caused an increase in annexin-V positive cells, activation of caspase-8, -9 and -3, dissipation of the mitochondrial membrane potential and enhancement of FAS protein level. Apoptosis induction triggered by this quinolinone was blocked by the pre-treatment of the cells with caspase-8, -9 and -3 inhibitors. The obtained results indicated that AJ-374-induced apoptosis was executed by both, the extrinsic and intrinsic pathways. The cytotoxic activity of AJ-374 was also associated with down-regulation of the mitogen-activated protein kinase (MAPK) pathway and was independent of reactive oxygen species generation. Taken together, these results suggest that AJ-374 exerts a potent anticancer effect on leukemia cells, with a wide safety margin, which makes this analog an attractive drug candidate for further testing.

中文翻译：

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新型合成喹啉酮衍生物诱导HL-60人白血病细胞凋亡的分子机制。

急性髓细胞性白血病的死亡率非常高，因此有必要寻找新的化疗候选药物。在这里，我们研究了一种新的合成化合物2-乙基-3-亚甲基-1-甲苯磺酰基-2,3-二氢喹啉-4-（1H）-one（AJ-374）对髓样白血病HL-60细胞的抗癌潜力。线。基于其对HL-60细胞的强抗增殖活性和对健康HUVEC细胞低30倍的细胞毒性，从合成的二氢喹啉酮的小型文库中选择该类似物。在最初的24小时内，AJ-374促进了细胞周期subG0 / G1期的细胞停滞。用AJ-374处理HL-60细胞会导致膜联蛋白V阳性细胞增加，caspase-8，-9和-3激活，线粒体膜电位消散以及FAS蛋白水平提高。用半胱天冬酶8，-9和-3抑制剂预处理可阻止由该喹啉酮引发的凋亡诱导。获得的结果表明，AJ-374诱导的凋亡是通过外在途径和内在途径两者执行的。AJ-374的细胞毒活性还与有丝分裂原激活的蛋白激酶（MAPK）通路的下调有关，并且与活性氧的产生无关。综上所述，这些结果表明，AJ-374对白血病细胞具有有效的抗癌作用，并且具有很宽的安全系数，这使得该类似物成为进一步测试的有吸引力的候选药物。外在和内在的途径。AJ-374的细胞毒活性还与有丝分裂原激活的蛋白激酶（MAPK）通路的下调有关，并且与活性氧的产生无关。综上所述，这些结果表明，AJ-374对白血病细胞具有有效的抗癌作用，并且具有很宽的安全系数，这使得该类似物成为进一步测试的有吸引力的候选药物。外在和内在的途径。AJ-374的细胞毒活性还与有丝分裂原激活的蛋白激酶（MAPK）通路的下调有关，并且与活性氧的产生无关。综上所述，这些结果表明，AJ-374对白血病细胞具有有效的抗癌作用，并且具有很宽的安全系数，这使得该类似物成为进一步测试的有吸引力的候选药物。