Molecular pharmacological studies on anti-tumor activity of direct oral anticoagulants (DOACs)

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08850
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Suzuka University of Medical Science
• Principal Investigator: SUZUKI Koji 鈴鹿医療科学大学, 薬学部, 教授 (70077808)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 抗凝固薬 / DOACs / Xa因子阻害薬 / Xa因子受容体 / 抗腫瘍作用 / 大腸癌細胞

Outline of Final Research Achievements

Direct oral anticoagulants (DOACs) are widely used as preventive agents for cerebral thromboembolism due to atrial fibrillation and deep vein thrombosis of the lower extremities. In this study, we analyzed the antitumor effects of DOACs. Anti-thrombin DOAC (dabigatran etexilate) and anti-Xa DOAC (edoxaban [EDX] and ribaroxaban) are orally administered daily to tumor-bearing BALB/c mice to which colon cancer Colon26 cells have been inoculated, and blood and tumor tissues are obtained from the mice on day 21 were collected and analyzed. As a result, EDX dose-dependently and significantly suppressed the tumor growth, the expression of plasma levels of IL-6, MMP-2 and tissue factor which induce coagulation and inflammation in host mice, the expression of tissue levels of factor Xa receptor PAR2 and various cancer cell proliferation related factors. EDX also promoted apoptosis of tumor tissue cells. These findings suggest that EDX may be used as a new antitumor agent.

Free Research Field

血栓止血学

Academic Significance and Societal Importance of the Research Achievements

癌患者数は増加の一途にあり、これまでにない新しい視点からの癌の発生や増殖・転移阻止の方策の確立が求められている。私はこれまでの研究で、血液の流動性維持に重要な凝固制御因子が癌細胞の増殖や転移を抑制する可能性を示してきた。そこで本研究では、癌細胞の増殖に及ぼす直接経口抗凝固薬DOACsの影響を解析した。その結果、DOACsの一つEDXが凝固第Xa因子受容体の活性化を阻害して癌細胞の増殖を著しく抑制するとともに、EDXが腫瘍組織のアポトーシスを誘導し、抗腫瘍作用を示すことを明らかにした。本研究成果は独創的で学術的にも重要であり、癌制御に向けた社会的意義は非常に大きいと考えられる。