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

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.