Ptotective effect of xanthine derivatives on colitis-associated dysplasia

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kurume University
• Principal Investigator: Mizoguchi Emiko 久留米大学, 医学部, 教授 (40782157)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: Chitinase 3-like 1 / 炎症性腸疾患 / 上皮異形成 / キサンチン誘導体 / カフェイン / ペントキシフィリン / 核局在配列

Outline of Final Research Achievements

Previously, our group has reported that caffeine (CAF), one of the xanthine-derivatives, suppresses inflammation by inhibiting pan-chitinases including enzymatically inactive chitinase 3-like 1 (CHI3L1), in a dextran sodium sulfate (DSS)-induced acute colitis. In this study, we have examined anti-neoplastic effect of CAF and/or PTXN in an Azoxymethane (AOM)-induced chronic colitis-associated cancer model. AOM was intraperitoneally administered to 8-week-old C57Bl/6 mice for 6 times, and these mice were sacrificed 5 weeks after the final administration of AOM. The mice were treated with CAF, PTXN or dH2O for 8 times intraperitoneally. Both CAF and PTXN administered mice cause severe adverse effects (e.g. shock death), so we suspended further experiment in this group. In an AOM-induced colonic cancer model, PTXN-treated mice significantly reduced the incidence of tumor multiplicity as well as tumor size as compared to the other two groups. PTXN may have an anti-neoplastic effect.

Free Research Field

癌免疫生物学、粘膜免疫学、消化器内科学

Academic Significance and Societal Importance of the Research Achievements

近年、日本における大腸癌と潰瘍性大腸炎やクローン病を含む炎症性腸疾患の罹患率が増加の一途をたどっている。特に大腸癌は最も予後不良な固形癌の一つである。我々のグループは、酵素活性を持たないタイプの哺乳類キチナーゼの一種であるCHI3L1が急性・慢性炎症時や大腸癌発症時に著しく増加し、その病態に深く関与することを報告してきた。興味深いことに、キサンチン誘導体の一種であるCAF とPTXNがCHI3L1の発現とその機能を抑制することがわかった。特にPTXNは、AOM誘導性の腸管上皮異形成に伴う大腸腫瘤数および腫瘤の大きさをCAFよりも有意に抑制したことから、将来的に臨床応用の可能性が期待できる。