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CC BY 4.0 · TH Open 2023; 07(01): e1-e13
DOI: 10.1055/s-0042-1758855
Original Article

Edoxaban, a Factor Xa-Specific Direct Oral Anticoagulant, Significantly Suppresses Tumor Growth in Colorectal Cancer Colon26-Inoculated BALB/c Mice

Keiichi Hiramoto
1   Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka-city, Mie, Japan
,
Nobuyuki Akita
2   Department of Clinical Engineering, Faculty of Medical Engineering, Suzuka University of Medical Science, Suzuka-city, Mie, Japan
,
Junji Nishioka
3   Department of Clinical Nutrition, Faculty of Health Science, Suzuka University of Medical Science, Suzuka-city, Mie, Japan
,
Koji Suzuki
1   Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka-city, Mie, Japan
› Author Affiliations Funding This work was supported by the Japan Society for the Promotion of Science (grant numbers 16K08633 and 19K08850).
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Abstract

Introduction Certain low-molecular-weight heparins have been reported to reduce tumor growth and metastasis in tumor cell-inoculated mouse models and cancer patients. Recently, direct oral anticoagulants (DOACs) have been widely used in patients with thromboembolism. This study was aimed at investigating the effect of DOACs, which target thrombin or factor Xa, on tumor growth in a syngeneic mouse model comprising BALB/c mice inoculated with colon cancer Colon26 cells.

Materials and Methods DOACs targeting thrombin (dabigatran etexilate [DABE]) or factor Xa (rivaroxaban [RVX] and edoxaban [EDX]) were orally administered daily to male BALB/c mice inoculated with Colon26 cells, followed by analyses of tumor growth and plasma levels of coagulation- and tumor-related factors such as tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6), and matrix metalloproteinase-2 (MMP-2).

Results Colon26 cells expressed significant amounts of functionally active TF. Tumor growth in Colon26-inoculated mice was significantly suppressed in DABE- or RVX-treated mice (p <0.05) and was suppressed more significantly in EDX-treated mice (p <0.01). Therefore, the antitumor mechanism of action of EDX was investigated next. Plasma levels of TF, PAI-1, IL-6, and MMP-2 were elevated in Colon26-inoculated mice but were significantly reduced in EDX-treated mice (p <0.01). The expression of protease-activated receptor (PAR)1, PAR2, signal transducer and activator of transcription-3 (STAT3), cyclin D1, and Ki67 was increased in tumor tissue of Colon26-inoculated mice but (except for PAR1) was significantly decreased in tumor tissues of EDX-treated mice (p <0.01). In addition, apoptotic cells and p53 protein levels were significantly increased in tumor tissues of EDX-treated mice.

Conclusion The data suggest that among the tested DOACs, EDX significantly suppresses tumor cell proliferation via the factor Xa-PAR2 pathway, which is activated by coagulation and inflammation in Colon26-inoculated mice and induces tumor cell apoptosis.

Keywords

DOAC - edoxaban - PAR2 - Colon26 cells - tumor growth - BALB/c mice

Supplementary Material



Publication History

Received: 30 June 2022

Accepted: 10 October 2022

Article published online:
07 January 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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