This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, R. Articles by Jing, Y. Search for Related Content PubMed PubMed Citation Articles by Wang, R. Articles by Jing, Y.

Ethacrynic Acid Butyl-Ester Induces Apoptosis in Leukemia Cells through a Hydrogen Peroxide–Mediated Pathway Independent of Glutathione S-Transferase P1-1 Inhibition

¹ Shenyang Pharmaceutical University, Shenyang, China; ² School of Pharmacy, Shandong University, Jinan, China; and ³ Mount Sinai School of Medicine, New York, New York

Requests for reprints: Yongkui Jing, Division of Hematology/Oncology, Department of Medicine, Box 1178, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6547. Phone: 212-241-6775; Fax: 212-996-5787; E-mail: yongkui.jing{at}mssm.edu.

Ethacrynic acid (EA), a glutathione S-transferase inhibitor and diuretic agent, inhibits cell growth and induces apoptosis in cancer cells. To improve the activities, the structure of EA has been modified, and it has been shown that EA esters had an increased cell growth inhibitory ability compared with nonesterified analogue. EA butyl-ester (EABE) was synthesized, and its apoptosis induction ability was studied. The efficacy of EABE was compared with that of EA, and the mechanisms of action were studied in HL-60 leukemia cells. EABE exhibited greater cell growth inhibitory and apoptosis induction abilities than did EA. EABE-induced apoptosis in HL-60 cells correlated with increased levels of reactive oxygen species, the death receptor 5 (DR5), and caspase activation and decreased levels of the mitochondrial membrane potential. Pretreatment with antioxidants, either N-acetylcysteine or catalase, completely blocked EABE-induced apoptosis, H₂O₂ accumulation, and up-regulation of DR5 levels. RG19, a subclone of Raji cells stably transfected with a GST expression vector, and K562 cells with high endogenous GSTP1-1 activity were less sensitive to EABE-induced apoptosis. EABE was more rapidly taken up than EA by HL-60 cells as determined by high-performance liquid chromatography (HPLC) measurements of intracellular concentrations. These results suggest that (a) H₂O₂ production is a mediator of EABE and EA-induced apoptosis; (b) GSTP1-1 plays a negative role in EABE and EA-induced apoptosis; and (c) the activity of EABE is greater than EA due to its more rapid entry into cells. [Cancer Res 2007;67(16):7856–64]