PMID- 19074830
OWN - NLM
STAT- MEDLINE
DCOM- 20090202
LR  - 20131121
IS  - 1541-7786 (Print)
IS  - 1541-7786 (Linking)
VI  - 6
IP  - 12
DP  - 2008 Dec
TI  - Anti-gout agent allopurinol exerts cytotoxicity to human hormone-refractory 
      prostate cancer cells in combination with tumor necrosis factor-related 
      apoptosis-inducing ligand.
PG  - 1852-60
LID - 10.1158/1541-7786.MCR-08-0012 [doi]
AB  - 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.
FAU - Yasuda, Takashi
AU  - Yasuda T
AD  - Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical 
      Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, 
      Kamigyo-ku, Kyoto, Japan.
FAU - Yoshida, Tatsushi
AU  - Yoshida T
FAU - Goda, Ahmed E
AU  - Goda AE
FAU - Horinaka, Mano
AU  - Horinaka M
FAU - Yano, Kimihiro
AU  - Yano K
FAU - Shiraishi, Takumi
AU  - Shiraishi T
FAU - Wakada, Miki
AU  - Wakada M
FAU - Mizutani, Yoichi
AU  - Mizutani Y
FAU - Miki, Tsuneharu
AU  - Miki T
FAU - Sakai, Toshiyuki
AU  - Sakai T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cancer Res
JT  - Molecular cancer research : MCR
JID - 101150042
RN  - 0 (Antimetabolites)
RN  - 0 (DDIT3 protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNF-Related Apoptosis-Inducing Ligand)
RN  - 0 (TNFSF10 protein, human)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 63CZ7GJN5I (Allopurinol)
RN  - EC 1.17.3.2 (Xanthine Oxidase)
SB  - IM
MH  - Allopurinol/*pharmacology
MH  - Antimetabolites/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm
MH  - Drug Therapy, Combination
MH  - Endoplasmic Reticulum/metabolism
MH  - Flow Cytometry
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Male
MH  - Promoter Regions, Genetic/physiology
MH  - Prostatic Neoplasms/*drug therapy/pathology
MH  - RNA, Small Interfering
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/metabolism
MH  - Response Elements
MH  - TNF-Related Apoptosis-Inducing Ligand/*pharmacology
MH  - Transcription Factor CHOP/genetics
MH  - Up-Regulation/drug effects
MH  - Xanthine Oxidase/genetics
EDAT- 2008/12/17 09:00
MHDA- 2009/02/03 09:00
CRDT- 2008/12/17 09:00
PHST- 2008/12/17 09:00 [entrez]
PHST- 2008/12/17 09:00 [pubmed]
PHST- 2009/02/03 09:00 [medline]
AID - 6/12/1852 [pii]
AID - 10.1158/1541-7786.MCR-08-0012 [doi]
PST - ppublish
SO  - Mol Cancer Res. 2008 Dec;6(12):1852-60. doi: 10.1158/1541-7786.MCR-08-0012.