Sulfasalazine, a therapeutic agent for ulcerative colitis, inhibits the growth of CD44v9+ cancer stem cells in ulcerative colitis-related cancer

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Abstract

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.

Original languageEnglish
JournalClinics and Research in Hepatology and Gastroenterology
DOIs
Publication statusAccepted/In press - 2015

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Sulfasalazine
Neoplastic Stem Cells
Ulcerative Colitis
Growth
Neoplasms
Therapeutics
Adenocarcinoma
Amino Acid Transport System X-AG
Cystine
Differentiation Antigens
Cadherins
Colorectal Neoplasms
Oxidative Stress
Anti-Inflammatory Agents
Immunohistochemistry

ASJC Scopus subject areas

  • Gastroenterology

Cite this

@article{ae7ed9516122403cbb3b2f7ffdadcb26,
title = "Sulfasalazine, a therapeutic agent for ulcerative colitis, inhibits the growth of CD44v9+ cancer stem cells in ulcerative colitis-related cancer",
abstract = "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.",
author = "Ryo Seishima and Koji Okabayashi and Osamu Nagano and Hirotoshi Hasegawa and Masashi Tsuruta and Masayuki Shimoda and Kaori Kameyama and Hideyuki Saya and Yuukou Kitagawa",
year = "2015",
doi = "10.1016/j.clinre.2015.11.007",
language = "English",
journal = "Clinics and Research in Hepatology and Gastroenterology",
issn = "2210-7401",
publisher = "Elsevier Masson",

}

TY - JOUR

T1 - Sulfasalazine, a therapeutic agent for ulcerative colitis, inhibits the growth of CD44v9+ cancer stem cells in ulcerative colitis-related cancer

AU - Seishima, Ryo

AU - Okabayashi, Koji

AU - Nagano, Osamu

AU - Hasegawa, Hirotoshi

AU - Tsuruta, Masashi

AU - Shimoda, Masayuki

AU - Kameyama, Kaori

AU - Saya, Hideyuki

AU - Kitagawa, Yuukou

PY - 2015

Y1 - 2015

N2 - 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.

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.

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U2 - 10.1016/j.clinre.2015.11.007

DO - 10.1016/j.clinre.2015.11.007

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JO - Clinics and Research in Hepatology and Gastroenterology

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SN - 2210-7401

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