Article

LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK–eIF2α–ATF4–CHOP axis

Authors: Xiao-xuan Yu1,2, Meng-yuan Zhu1, Jia-rong Wang1, Hui Li1, Po Hu1, Ying-jie Qing1, Xiang-yuan Wang1, Hong-zheng Wang1, Zhan-yu Wang1, Jing-yan Xu3, Qing-long Guo1, Hui Hui1
1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China
2 Department of Pharmacology, School of Medicine & Holostic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
3 Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing 210000, China
Correspondence to: Qing-long Guo: anticancer_drug@163.com, Hui Hui: moyehh@163.com,
DOI: 10.1038/s41401-020-0466-7
Received: 20 April 2020
Accepted: 22 June 2020
Advance online: 3 August 2020

Abstract

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress- related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent
against CTCL.
Keywords: CTCL; LW-213; wogonin; flavonoids; ER stress; ROS; calcium; apoptosis; NAC; 2-APB

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