LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.
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.
['Yu|Xiao-Xuan|XX|', 'Zhu|Meng-Yuan|MY|', 'Wang|Jia-Rong|JR|', 'Li|Hui|H|', 'Hu|Po|P|', 'Qing|Ying-Jie|YJ|', 'Wang|Xiang-Yuan|XY|', 'Wang|Hong-Zheng|HZ|', 'Wang|Zhan-Yu|ZY|', 'Xu|Jing-Yan|JY|', 'Guo|Qing-Long|QL|', 'Hui|Hui|H|']
D051701:Activating Transcription Factor 4 D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D045744:Cell Line, Tumor D004305:Dose-Response Relationship, Drug D015852:Eukaryotic Initiation Factor-2 D005260:Female D044950:Flavanones D006801:Humans D020128:Inhibitory Concentration 50 D016410:Lymphoma, T-Cell, Cutaneous D051379:Mice D016688:Mice, Inbred NOD D016513:Mice, SCID D017382:Reactive Oxygen Species D012878:Skin Neoplasms D051742:Transcription Factor CHOP D023041:Xenograft Model Antitumor Assays D019892:eIF-2 Kinase
LW-213 apoptosis CTCL wogonin ROS calcium NAC 2-APB ER stress flavonoids