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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Anti-gout agent allopurinol exerts cytotoxicity to human hormone-refractory prostate cancer cells in combination with tumor necrosis factor-related apoptosis-inducing ligand
Molecular Cancer Research, Volume 6, No. 12, Year 2008
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Description
Allopurinol has been used for the treatment of gout and conditions associated with hyperuricemia for several decades. We explored the potential of allopurinol on cancer treatment. Allopurinol did not expose cytotoxicity as a single treatment in human hormone refractory prostate cancer cell lines, PC-3 and DU145. However, allopurinol drastically induced apoptosis of PC-3 and DU145 in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is a promising candidate for anticancer agent but its efficacy is limited by the existence of resistant cancer cells. We examined the underlying mechanism by which allopurinol overcomes the resistance of prostate cancer cells to TRAIL. Allopurinol up-regulated the expression of a proapoptotic TRAIL receptor, death receptor 5 (DR5). Allopurinol increased DR5 protein, mRNA, and promoter activity. Using DR5 small interfering RNA (siRNA), we showed that allopurinol-mediated DR5 up-regulation contributed to the enhancement of TRAIL effect by allopurinol. Furthermore, we examined the mechanism of allopurinol-mediated DR5 up-regulation. DR5 promoter activity induced by allopurinol was diminished by a mutation of a CAAT/enhancer binding protein homologous protein (CHOP)-binding site. In addition, allopurinol also increased CHOP expression, suggesting that allopurinol induced DR5 expression via CHOP. Allopurinol possesses the activity of a xanthine oxidase (XO) inhibitor. We used XO siRNA instead of allopurinol. XO siRNA also up-regulated DR5 and CHOP expression and sensitized the prostate cancer cells to TRAIL-induced apoptosis. Here, we show the novel potential of allopurinol in cancer treatment and indicate that the combination of allopurinol with TRAIL is effective strategy to expand the TRAIL-mediated cancer therapy. Copyright © 2008 American Association for Cancer Research.
Authors & Co-Authors
Yasuda, Takashi
Japan, Kyoto
Graduate School of Medical Science
Yoshida, Tatsushi
Japan, Kyoto
Graduate School of Medical Science
Goda, Ahmed E.
Japan, Kyoto
Graduate School of Medical Science
Egypt, Tanta
Faculty of Pharmacy
Horinaka, Mano
Japan, Kyoto
Graduate School of Medical Science
Yano, Kimihiro
Japan, Kyoto
Graduate School of Medical Science
Shiraishi, T.
Japan, Kyoto
Graduate School of Medical Science
Wakada, Miki
Japan, Kyoto
Graduate School of Medical Science
Mizutani, Yoichi
Japan, Kyoto
Graduate School of Medical Science
Miki, Tsuneharu
Japan, Kyoto
Graduate School of Medical Science
Sakai, Toshiyuki
Japan, Kyoto
Graduate School of Medical Science
Statistics
Citations: 37
Authors: 10
Affiliations: 2
Identifiers
Doi:
10.1158/1541-7786.MCR-08-0012
ISSN:
15417786
Research Areas
Cancer