Drug Design, Development and Therapy (Aug 2022)
The Flavagline Compound 1-(2-(dimethylamino)acetyl)-Rocaglaol Induces Apoptosis in K562 Cells by Regulating the PI3K/Akt/mTOR, JAK2/STAT3, and MAPK Pathways
Abstract
Xinmei Yang,1– 3 Xijun Wu,4 Xiaosen Wu,5 Lei Huang,1,2 Jingrui Song,1,2 Chunmao Yuan,1,2 Zhixu He,3,6 Yanmei Li1,2 1State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, People’s Republic of China; 2The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, Guizhou Medical University, Guiyang, 550014, People’s Republic of China; 3Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, 550004, People’s Republic of China; 4Department of Laboratory, The Affiliated Jinyang Hospital of Guizhou Medical University, Guiyang, 550023, People’s Republic of China; 5FuRong Tobacco Research Station, Xiangxi Autonomous Prefecture Tobacco Company Yongshun Branch, Yongshun, 416700, People’s Republic of China; 6Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, Guiyang, 550001, People’s Republic of ChinaCorrespondence: Yanmei Li, State Key Laboratory for Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, People’s Republic of China, Tel/Fax +86 85183805081, Email [email protected] Zhixu He, Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, 550004, People’s Republic of China, Tel/Fax +86 13595019670, Email [email protected]: Chronic myelogenous leukemia (CML) is a hematological malignancy with increased proliferation of cells of the myeloid series. This can disrupt normal hematopoiesis. The 1-(2-(dimethylamino)acetyl)-rocaglaol (MQ-16) is a new synthetic flavagline compound that showed promising activity in chronic myeloid leukemia K562 cells. This study aims to analyze the underlying mechanisms of MQ-16 against CML.Methods: Growth, cell cycle progression, and apoptosis were assessed in K562 cells following MQ-16 exposure by MTT assay and flow cytometry. The effect of MQ-16 on DNA strands between nucleosomes was examined by 1% agarose gel electrophoresis. PI3K/Akt/mTOR, JAK2/STAT3, and mitogen-activated protein kinase (MAPK) pathway-related proteins were detected in MQ-16–treated K562 cells by Western blot.Results: MQ-16 significantly inhibited the proliferation of K562 cells and arrested the cell cycle at the G2/M phase in a time- and concentration-dependent manner. MQ-16 induced mitochondria-dependent apoptosis by downregulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and induced time- and concentration-dependent DNA fragmentation. In addition, MQ-16 affected the expression of PI3K/Akt/mTOR, JAK2/STAT3, and MAPK pathway-related proteins.Conclusion: In summary, MQ-16 appears to be a promising chemotherapeutic drug for treating CML.Keywords: CML, flavagline, cycle arrest, apoptosis, PI3K/Akt/mTOR, JAK2/STAT3, MAPK
