title: Anti-gout agent allopurinol exerts cytotoxicity to human hormone-refractory prostate cancer cells in combination with tumor necrosis factor-related apoptosis-inducing ligand.
abstract: 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.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yasuda
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Goda
authors.forename: Mano
authors.initials: M
authors.lastname: Horinaka
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Yano
authors.forename: Takumi
authors.initials: T
authors.lastname: Shiraishi
authors.forename: Miki
authors.initials: M
authors.lastname: Wakada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizutani
authors.forename: Tsuneharu
authors.initials: T
authors.lastname: Miki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000493:Allopurinol / Q000494:pharmacology*; D000963:Antimetabolites / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000235:genetics
chemical_list: D000963:Antimetabolites; C497249:DDIT3 protein, human; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051742:Transcription Factor CHOP; D000493:Allopurinol; D014969:Xanthine Oxidase