Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Paeonol enhances TRAIL-induced apoptosis of human lung cancer cells by upregulating death receptors-4 and 5 via ROS-JNK/ERK-CHOP signaling

Yanqing Fan¹, Xiaoyan Chen², Guizhi Zhang³

¹The Third Affiliated Hospital of Kunming Medical University, Kunming 650106; ²Department of Western Medicine Education, Shandong College of Traditional Chinese Medicine, Yantai 264199; ³College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei 43 0065, China.

For correspondence:- Guizhi Zhang Email: edsklt@163.com

Accepted: 19 February 2021 Published: 31 March 2021

Citation: Fan Y, Chen X, Zhang G. Paeonol enhances TRAIL-induced apoptosis of human lung cancer cells by upregulating death receptors-4 and 5 via ROS-JNK/ERK-CHOP signaling. Trop J Pharm Res 2021; 20(3):467-473 doi: 10.4314/tjpr.v20i3.4

© 2021 The authors.
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited..

Abstract

Purpose: To study the anti-proliferative potential of paeonol against lung cancer cells, and investigate its mechanism of action.

Methods: Cell viability after paeonol treatment was determined with 3-(4,5-dimethylthiazol-2yl)2,5-diphenyltetrazolium bromide (MTT) assay, while paeonol- and TRAIL-mediated apoptosis was assayed using flow cytometry. Western blotting was used to assay the protein expression levels of phosphorylated JNK and ERK1/2, as well as protein expressions of pro-apoptotic factors/death receptors. 2′,7′-Dichlorodihydrofluorescein diacetate (H2DCFDA) staining and flow cytometry were used to monitor paeonol-induced reactive oxygen species (ROS) in the cells.

Results: Paeonol treatment markedly reduced the proliferations of H1975 and BGC823 cells (p < 0.05). In H1975 and BGC823 cells, paeonol/TRAIL combination increased apoptosis to 88.43 and 87.21 %, respectively (p < 0.05). The levels of death receptor 4 (DR4) and death receptor 5 (DR5) were increased significantly by paeonol, relative to the control (p < 0.05). Paeonol also reduced the levels of decoy receptor-1 (DcR1) and decoy receptor-2 (DcR2), and increased the expression of CHOP (p < 0.05). The protein expression levels of survivin, Bcl-2, cFLIP and Bcl-xL were decreased, while protein levels of caspase3, caspase-8 and caspase-9 were upregulated by paeonol. Moreover, paeonol significantly upregulated p-ERK and p-JNK in H1975 and BGC823 cells, and also increased ROS levels, when compared to control (p < 0.05).

Conclusion: Paeonol exerts anti-proliferative potential on lung cancer cells through upregulation of death receptors, activation of JNK/ERK-CHOP pathway and generation of ROS. Therefore, paeonol has a therapeutic potential for the management of lung cancer.

Keywords: Paeonol, Proliferation, Reactive oxygen species, Apoptosis, Tumour necrosis factor