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Edoxaban, a Factor Xa-Specific Direct Oral Anticoagulant, Significantly Suppresses Tumor Growth in Colorectal Cancer
Keiichi Hiramoto1, Nobuyuki Akita2, Junji Nishioka3
1Department of Molecular Pathobiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka-city, Mie, Japan.
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.
Insights
Direct oral anticoagulants (DOACs) like edoxaban (EDX) show promise in cancer treatment. EDX significantly suppresses colon cancer growth by targeting the factor Xa-PAR2 pathway, inducing apoptosis.
Area of Science:
- Pharmacology
- Oncology
- Hematology
Background:
- Low-molecular-weight heparins have demonstrated antitumor properties.
- Direct oral anticoagulants (DOACs) are increasingly used for thromboembolism.
- The potential anticancer effects of DOACs warrant investigation.
Purpose of the Study:
- To investigate the impact of DOACs targeting thrombin or factor Xa on tumor growth.
- To evaluate the antitumor mechanisms of edoxaban (EDX) in a colon cancer model.
Main Methods:
- Colon26 colon cancer cells were inoculated into BALB/c mice.
- Mice were treated with dabigatran etexilate (DABE), rivaroxaban (RVX), or edoxaban (EDX).
- Tumor growth, coagulation factors (tissue factor - TF), and inflammatory markers (PAI-1, IL-6, MMP-2) were analyzed.
Main Results:
- DABE, RVX, and EDX significantly suppressed tumor growth, with EDX showing the most significant effect.
- EDX treatment reduced elevated plasma levels of TF, PAI-1, IL-6, and MMP-2.
- EDX decreased the expression of PAR2, STAT3, cyclin D1, and Ki67 in tumor tissues, while increasing apoptosis and p53 levels.
Conclusions:
- Edoxaban (EDX) significantly inhibits colon cancer cell proliferation and induces apoptosis.
- The antitumor effect of EDX is mediated through the factor Xa-PAR2 pathway.
- DOACs, particularly EDX, represent a potential therapeutic strategy for cancer treatment.
