扁柏黄酮通过MAPK/NF-κB信号通路诱导慢性髓性白血病细胞凋亡、细胞周期阻滞和自噬。

Hinokiflavone induces apoptosis, cell cycle arrest and autophagy in chronic myeloid leukemia cells through MAPK/NF-κB signaling pathway.

作者信息

Qin Xiang, Chen Xi, Guo Ling, Liu Jing, Yang You, Zeng Yan, Li Cheng, Liu Wenjun, Ma Wenzhe

机构信息

State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau, China.

Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Children Hematological Oncology and Birth Defects Laboratory, Sichuan Clinical Research Center for Birth Defects, No. 25, Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan, China.

出版信息

BMC Complement Med Ther. 2022 Apr 6;22(1):100. doi: 10.1186/s12906-022-03580-7.

BACKGROUND

Chronic myeloid leukemia (CML) is a myeloproliferative tumor originating from hematopoietic stem cells, and resistance to tyrosine kinase inhibitors (TKI) has become a major cause of treatment failure. Alternative drug therapy is one of the important ways to overcome TKI resistance. Hinokiflavone (HF) is a C-O-C type biflavonoid with low toxicity and antitumor activity. This study investigated the antitumor effect and possible mechanisms of HF in CML cells.

METHODS

Cell viability was measured by CCK-8 assay. Cell apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blotting was used to assess protein expression levels.

RESULTS

Our results showed that HF significantly inhibited the viability of K562 cells in a concentration- and time-dependent manner and induced G/M phase arrest by up-regulating p21 and down-regulating Cdc2 protein. Furthermore, HF induced caspase-dependent apoptosis by activating JNK/p38 MAPK signaling pathway and inhibiting NF-κB activity. In addition, HF induced autophagy by increasing LC3-II expression and p62 degradation. Pretreatment with CQ, a late autophagy inhibitor, significantly increased the levels of LC3-II and p62 proteins and promoted cell survival.

CONCLUSION

HF shows a good anti-leukemia effect and is expected to become a potential therapeutic drug for CML.

背景

慢性髓性白血病（CML）是一种起源于造血干细胞的骨髓增殖性肿瘤，对酪氨酸激酶抑制剂（TKI）耐药已成为治疗失败的主要原因。替代药物治疗是克服TKI耐药的重要途径之一。扁柏黄酮（HF）是一种具有低毒性和抗肿瘤活性的C-O-C型双黄酮。本研究探讨了HF对CML细胞的抗肿瘤作用及其可能机制。

方法

采用CCK-8法检测细胞活力。通过流式细胞术分析细胞凋亡和细胞周期分布。采用蛋白质印迹法评估蛋白表达水平。

结果

我们的结果表明，HF以浓度和时间依赖性方式显著抑制K562细胞的活力，并通过上调p21和下调Cdc2蛋白诱导G/M期阻滞。此外，HF通过激活JNK/p38 MAPK信号通路和抑制NF-κB活性诱导caspase依赖性凋亡。此外，HF通过增加LC3-II表达和p62降解诱导自噬。晚期自噬抑制剂CQ预处理显著增加了LC3-II和p62蛋白水平并促进细胞存活。