PMID- 26775891
OWN - NLM
STAT- MEDLINE
DCOM- 20180117
LR  - 20180117
IS  - 2210-741X (Electronic)
IS  - 2210-7401 (Linking)
VI  - 40
IP  - 4
DP  - 2016 Sep
TI  - Sulfasalazine, a therapeutic agent for ulcerative colitis, inhibits the growth of 
      CD44v9(+) cancer stem cells in ulcerative colitis-related cancer.
PG  - 487-93
LID - S2210-7401(15)00288-0 [pii]
LID - 10.1016/j.clinre.2015.11.007 [doi]
AB  - BACKGROUND AND OBJECTIVE: Sulfasalazine reduces the risk of ulcerative colitis 
      (UC)-related cancer through its anti-inflammatory effect and induction of 
      oxidative stress in cancer cells by inhibiting the glutamate-cystine transporter, 
      which is closely associated with the cancer stem cell surface marker CD44v9. This 
      study aimed to quantify the effects of sulfasalazine on CD44v9 expression and 
      pathological factors in colorectal cancers (CRCs) arising from UC. METHODS: 
      Twenty-six patients with UC-related cancer were classified into groups according 
      to the length of sulfasalazine treatment as follows: (1) long-term (LT) 
      (>/= 5 years) and (2) short-term (ST) (< 5 years). Using immunohistochemistry, we 
      compared CD44v9 and Ki-67 expression and pathological characteristics of each 
      group's tumors. In vitro assay was performed to investigate the effect of 
      sulfasalazine on epithelial differentiation and proliferation of CD44(+) cancer 
      cells. RESULTS: Immunohistochemical analysis revealed that CD44v9 expression 
      tended to be lower in the LT group (LT:ST=15.4%:46.2%, P=0.20), and Ki-67/CD44v9 
      double-stained cells were significantly lower in the LT group (LT:ST=0%:6.9%, 
      P=0.01). Pathologically, the frequency of well-differentiated adenocarcinomas was 
      higher in the LT group (LT:ST=84.6%:38.5%, P=0.04). In vitro assay revealed that 
      sulfasalazine promoted the expression of epithelial differentiation markers 
      (E-cadherin and CDX2) and inhibited the proliferation of CD44(+) cancer cells. 
      CONCLUSIONS: Long-term sulfasalazine administration reduced proliferative 
      CD44v9(+) cells and increased the degree of differentiation of adenocarcinomas. 
      These findings indicate the importance of CD44v9(+) cells in UC-related cancer 
      progression and suggest that sulfasalazine may serve as a novel therapeutic agent 
      that targets CD44v9(+) cells.
CI  - Copyright (c) 2015 Elsevier Masson SAS. All rights reserved.
FAU - Seishima, Ryo
AU  - Seishima R
AD  - Department of surgery, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan; Division of gene regulation, institute for 
      advanced medical research, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan.
FAU - Okabayashi, Koji
AU  - Okabayashi K
AD  - Department of surgery, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan. Electronic address: okabayashikoji@gmail.com.
FAU - Nagano, Osamu
AU  - Nagano O
AD  - Division of gene regulation, institute for advanced medical research, Keio 
      university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, 
      Japan.
FAU - Hasegawa, Hirotoshi
AU  - Hasegawa H
AD  - Department of surgery, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan.
FAU - Tsuruta, Masashi
AU  - Tsuruta M
AD  - Department of surgery, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan.
FAU - Shimoda, Masayuki
AU  - Shimoda M
AD  - Department of pathology, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan.
FAU - Kameyama, Kaori
AU  - Kameyama K
AD  - Department of pathology, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan.
FAU - Saya, Hideyuki
AU  - Saya H
AD  - Division of gene regulation, institute for advanced medical research, Keio 
      university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, 
      Japan.
FAU - Kitagawa, Yuko
AU  - Kitagawa Y
AD  - Department of surgery, Keio university school of medicine, 35, Shinano-machi, 
      1608582 Shinjuku-ku, Tokyo, Japan.
LA  - eng
PT  - Journal Article
DEP - 20160105
PL  - France
TA  - Clin Res Hepatol Gastroenterol
JT  - Clinics and research in hepatology and gastroenterology
JID - 101553659
RN  - 0 (CD44 protein, human)
RN  - 0 (CDX2 Transcription Factor)
RN  - 0 (CDX2 protein, human)
RN  - 0 (Cadherins)
RN  - 0 (Gastrointestinal Agents)
RN  - 0 (Hyaluronan Receptors)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (RNA, Messenger)
RN  - 3XC8GUZ6CB (Sulfasalazine)
SB  - IM
MH  - Adenocarcinoma/pathology
MH  - Adult
MH  - Aged
MH  - CDX2 Transcription Factor/metabolism
MH  - Cadherins/metabolism
MH  - Cell Differentiation/drug effects
MH  - Cell Proliferation/drug effects
MH  - Colitis, Ulcerative/drug therapy
MH  - Colorectal Neoplasms/*pathology
MH  - Down-Regulation
MH  - Female
MH  - Gastrointestinal Agents/*pharmacology
MH  - Humans
MH  - Hyaluronan Receptors/genetics/*metabolism
MH  - Immunohistochemistry
MH  - Ki-67 Antigen/metabolism
MH  - Male
MH  - Middle Aged
MH  - Neoplastic Stem Cells/*drug effects
MH  - RNA, Messenger/metabolism
MH  - Retrospective Studies
MH  - Sulfasalazine/*pharmacology
EDAT- 2016/01/19 06:00
MHDA- 2018/01/18 06:00
CRDT- 2016/01/19 06:00
PHST- 2015/05/19 00:00 [received]
PHST- 2015/09/05 00:00 [revised]
PHST- 2015/11/11 00:00 [accepted]
PHST- 2016/01/19 06:00 [entrez]
PHST- 2016/01/19 06:00 [pubmed]
PHST- 2018/01/18 06:00 [medline]
AID - S2210-7401(15)00288-0 [pii]
AID - 10.1016/j.clinre.2015.11.007 [doi]
PST - ppublish
SO  - Clin Res Hepatol Gastroenterol. 2016 Sep;40(4):487-93. doi: 
      10.1016/j.clinre.2015.11.007. Epub 2016 Jan 5.