Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells

Citation
H. Sakamoto et al., Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells, CLIN CANC R, 7(8), 2001, pp. 2513-2518
Citations number
24
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
1078-0432 → ACNP
Volume
7
Issue
8
Year of publication
2001
Pages
2513 - 2518
Database
ISI
SICI code
1078-0432(200108)7:8<2513:SAOAPB>2.0.ZU;2-C
Abstract
Purpose: Glyoxalase I (GLO1) is an enzyme that plays a role in the detoxifi cation of methylglyoxal, a side-product of glycolysis. We previously report ed that GLO1 was a resistant factor to antitumor agent-induced apoptosis, a nd that S-p-bromobenzylglutathione cyclopentyl diester (BBGC), an effective inhibitor of GLO1, selectively sensitized to etoposide the drug-resistant human leukemia cells that overexpressed GLO1 In this study, we quantitative ly measured GLO1 enzyme activity in various human solid tumor cells, and th e antiproliferative effect of the GLO1 inhibitor was examined. Experimental Design: BBGC-induced apoptosis was assessed by flow cytometry. To evaluate antitumor activity of BBGC in vivo, we developed human cancer xenografts in nude mice. Results: We found that GLO1 enzyme activity was higher in all of the 38 hum an cancer cell lines that we examined than in the normal tissue samples. Mo reover, GLO1 activity was frequently elevated in human lung carcinoma cells . Positive correlation between cellular GLO1 activity and BBGC sensitivity was observed in the lung cancer cell lines. Human lung cancer NCI-H522 and DMS114 cells, expressing higher GLO1 activity, underwent apoptosis when tre ated with BBGC, whereas A549 cells, expressing lower activity, did not. BBG C induced the activation of the stress-activated protein kinases c-jun NH2- terminal kinase 1 (JNK1) and p38 mitogen-activated protein kinase (MAPK), w hich led to caspase activation in GLO1-overexpressing tumor cells. BBGC sig nificantly inhibited the growth of xenografted DMS114 and human prostate ca ncer DU-145. Conclusions: Our present results indicate that GLO1 is a tumor-specific tar get enzyme especially in human lung carcinoma cells and that the GLO1 inhib itor is a potent chemotherapeutic agent to repress GLO1-overexpressing huma n tumors.