Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells.
OBJECTIVE
Glyoxalase I (GLO1) is an enzyme that plays a role in the detoxification of methylglyoxal, a side-product of glycolysis. We previously reported that GLO1 was a resistant factor to antitumor agent-induced apoptosis, and 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 quantitatively measured GLO1 enzyme activity in various human solid tumor cells, and the antiproliferative effect of the GLO1 inhibitor was examined.


METHODS
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 human cancer cell lines that we examined than in the normal tissue samples. Moreover, 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 treated with BBGC, whereas A549 cells, expressing lower activity, did not. BBGC induced the activation of the stress-activated protein kinases c-Jun NH(2)-terminal kinase 1 (JNK1) and p38 mitogen-activated protein kinase (MAPK), which led to caspase activation in GLO1-overexpressing tumor cells. BBGC significantly inhibited the growth of xenografted DMS114 and human prostate cancer DU-145.


CONCLUSIONS
Our present results indicate that GLO1 is a tumor-specific target enzyme especially in human lung carcinoma cells and that the GLO1 inhibitor is a potent chemotherapeutic agent to repress GLO1-overexpressing human tumors.
Sakamoto
H
H
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan.
Mashima
T
T
Sato
S
S
Hashimoto
Y
Y
Yamori
T
T
Tsuruo
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; C099177:S-4-bromobenzylglutathione cyclopentyl diester; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases; D007791:Lactoylglutathione Lyase; D005978:Glutathione