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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Lipoxygenase inhibitors induce death receptor 5/TRAIL-R2 expression and sensitize malignant tumor cells to TRAIL-induced apoptosis
Cancer Science, Volume 98, No. 9, Year 2007
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Description
Lipoxygenases induce malignant tumor progression and lipoxygenase inhibitors have been considered as promising anti-tumor agents. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. Combined treatment with nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, and TRAIL markedly induced apoptosis in Jurkat T-cell leukemia cells at suboptimal concentrations for each agent. The combined treatment efficiently activated caspase-3, -8 and -10, and Bid. The underling mechanism by which NDGA enhanced TRAIL-induced apoptosis was examined. NDGA did not change the expression levels of anti-apoptotic factors, Bcl-xL, Bcl-2, cIAP-1, XIAP and survivin. The expression of death receptor-related genes was investigated and it was found that NDGA specifically up-regulated the expression of death receptor 5 (DR5) at mRNA and protein levels. Down-regulation of DR5 by small interfering RNA prevented the sensitizing effect of NDGA on TRAIL-induced apoptosis. Furthermore, NDGA sensitized prostate cancer and colorectal cancer cells to TRAIL-induced apoptosis. In contrast, NDGA neither enhanced TRAIL-induced apoptosis nor up-regulated DR5 expression in normal peripheral blood mononuclear cells. Another lipoxygenase inhibitor, AA861, also up-regulated DR5 and sensitized Jurkat and DU145 cells to TRAIL. These results indicate that lipoxygenase inhibitors augment the apoptotic efficiency of TRAIL through DR5 up-regulation in malignant tumor cells, and raise the possibility that the combination of lipoxygenase inhibitor and TRAIL is a promising strategy for malignant tumor treatment. © 2007 Japanese Cancer Association.
Authors & Co-Authors
Yoshida, Tatsushi
Japan, Kyoto
Graduate School of Medical Science
Shiraishi, T.
Japan, Kyoto
Graduate School of Medical Science
Japan, Kyoto
Kyoto Prefectural University of Medicine
Horinaka, Mano
Japan, Kyoto
Graduate School of Medical Science
Nakata, Susumu
Japan, Kyoto
Graduate School of Medical Science
Yasuda, Takashi
Japan, Kyoto
Graduate School of Medical Science
Japan, Kyoto
Kyoto Prefectural University of Medicine
Goda, Ahmed E.
Japan, Kyoto
Graduate School of Medical Science
Egypt, Tanta
Faculty of Pharmacy
Wakada, Miki
Japan, Kyoto
Graduate School of Medical Science
Mizutani, Yoichi
Japan, Kyoto
Kyoto Prefectural University of Medicine
Miki, Tsuneharu
Japan, Kyoto
Kyoto Prefectural University of Medicine
Nishikawa, Akiyoshi
Japan, Tokyo
National Institute of Health Sciences Tokyo
Sakai, Toshiyuki
Japan, Kyoto
Graduate School of Medical Science
Statistics
Citations: 23
Authors: 11
Affiliations: 4
Identifiers
Doi:
10.1111/j.1349-7006.2007.00559.x
ISSN:
13479032
e-ISSN:
13497006
Research Areas
Cancer