Ethacrynic Oxadiazole 6u Induces Apoptosis by Targeting mTOR/c-Flip Axis and Noxa in Lymphoma Cells.

Authors

Yafei Kuang, Shuoyan Feng, Jinxiao Sun, Zhuomin Tan, Xuan Bao, Yongmi Huang, Yuetong Wang, Ping Gong, Samuel Waxman, Guisen Zhao, Jingyi Zhang, Yongkui Jing

Published in

Biological procedures online. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

Evasion of apoptosis is a major cause of therapy failure in lymphoma. We studied a covalent compound 6u with an α, β-saturated carbonyl group derived from the diuretic drug ethacrynic acid to induce apoptosis of lymphoma cells by targeting antiapoptotic proteins.
We found that 6u induces apoptosis in 4 lymphoma cell lines, Daudi, Romas, Jeko-1 and Jurkat, accompanied by down-regulation of c-Flip and Mcl-1, as well as upregulation of Noxa. The down-regulation of Mcl-1 relies on Noxa induction and that the down-regulation of c-Flip is mediated by inhibiting protein synthesis pathway through covalent binding to mTOR complexes. Overexpression of c-Flip and silencing Noxa attenuate 6u-induced apoptosis. 6u modified with the saturated carbonyl structure loses the mTOR inhibition and apoptosis induction abilities. 6u exhibits potent anti-lymphoma effects in mantle cell lymphoma Jeko-1 xenografts without causing toxicity.
6u functions as an apoptosis inducer through the α, β-saturated carbonyl group to decrease c-Flip and to induce Noxa. 6u represents a new type of covalent agent for targeting lymphoma by inducing apoptosis.

PMID:
42399755
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.

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