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

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• 作者：Ryo Seishima^a ; ^b ; Koji Okabayashi^a ; ^{okabayashikoji@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Osamu Nagano^b ; Hirotoshi Hasegawa^a ; Masashi Tsuruta^a ; Masayuki Shimoda^c ; Kaori Kameyama^c ; Hideyuki Saya^b ; Yuko Kitagawa^a
• 刊名：Clinics and Research in Hepatology and Gastroenterology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：40
• 期：4
• 页码：487-493
• 全文大小：1868 K

文摘

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.