School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China; Guizhou Provincial People's Hospital, Guiyang, 550002, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, 550014, China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang, 550014, China.
Biomed Pharmacother. 2018 Oct;106:794-804. doi: 10.1016/j.biopha.2018.06.153. Epub 2018 Jul 11.
Leukemia is a hematologic malignancy with poor prognosis in humans and chemotherapy is the main strategy for treating leukemia patients. Novel drugs with better selectivity and lower toxicity are required for the treatment of patients. A novel 3',5'-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3- pyridinyl)-propene-1-one (C10) is a potential new anti-leukemia agent. In this study, we investigated the molecular mechanisms of the anti-leukemia effects of C10 on different leukemia cells in vitro. C10 showed strong inhibition of proliferation of the human erythroleukemia cell line HEL and human myeloid leukemia cell line K562, and several cell and flow cytometer assays showed that inhibition by C10 was due to the regulation of gene expression or phosphorylation in the apoptosis and autophagy pathways. The results showed that C10 regulated the expression of Bax, c-Myc, Bcl-2, P38/AMPK and ERK 1/2, activated the expression of Caspase-3, -8, and PARP at the protein level in the apoptosis pathway of the two leukemia cell types, and inhibited the expression of erythroleukemia carcinogene Fli-1 in the human erythroleukemia cell line HEL. Additionally,treatment with the compound induced a time-dependent increase in expression of LC 3A/B via inhibiting the AKT-mTOR pathway, which is associated with cell autophagy. Taken together, the above results suggest that the novel synthesized 3',5'-diprenylated chalcone can prevent the growth of leukemia cells by inducing apoptosis and autophagy.
白血病是一种血液系统恶性肿瘤，人类预后较差，化疗是治疗白血病患者的主要策略。需要新型选择性更好、毒性更低的药物来治疗患者。一种新型的 3'，5'-二烯丙基查尔酮，（E）-1-（2-羟基-4-甲氧基-3,5-二烯丙基）苯基-3-（3-吡啶基）-1-丙烯-1-酮（C10）是一种有潜力的新型抗白血病药物。在这项研究中，我们研究了 C10 对体外不同白血病细胞的抗白血病作用的分子机制。C10 对人红白血病细胞系 HEL 和人髓样白血病细胞系 K562 的增殖有强烈的抑制作用，几种细胞和流式细胞仪检测表明，C10 的抑制作用是由于凋亡和自噬途径中基因表达或磷酸化的调节。结果表明，C10 调节 Bax、c-Myc、Bcl-2、P38/AMPK 和 ERK 1/2 的表达，在两种白血病细胞类型的凋亡途径中激活 Caspase-3、-8 和 PARP 的蛋白表达，并抑制人红白血病细胞系 HEL 中的红白血病致癌基因 Fli-1 的表达。此外，该化合物通过抑制 AKT-mTOR 通路诱导 LC 3A/B 的表达时间依赖性增加，与细胞自噬有关。综上所述，这些结果表明，新型合成的 3'，5'-二烯丙基查尔酮可以通过诱导细胞凋亡和自噬来阻止白血病细胞的生长。
