dHG-5 Exhibits Dual Efficacy of Anti-Metastatic and Anti-hypercoagulability in Mice by Inhibiting Heparanase and Intrinsic Coagulation Pathway.

Abstract

Introduction: Cancer metastasis and associated thrombosis are significant contributors to cancerrelated mortality, necessitating therapeutic strategies that simultaneously address both issues. This study aimed to evaluate the dual anti-metastatic and anti-hypercoagulability properties of dHG-5, a low-molecular-weight fucosylated glycosaminoglycan derived from the sea cucumber Holothuria fuscopunctata.

Methods: The heparanase-inhibitory and anticoagulant effects of dHG-5 were assessed in vitro using biochemical assays. The impact of dHG-5 on 4T1 cell migration and invasion was evaluated using Transwell assays. The antimetastatic and anti-hypercoagulability efficacy of dHG-5 was further tested in a 4T1 mammary carcinoma mouse model, with enoxaparin (LMWH) used as a control.

Results: dHG-5 exhibited potent heparanase inhibition (IC50 = 91.0 nM) and significantly reduced 4T1 cell migration and invasion at 4.0 μmol/L. In vivo, dHG-5 reduced lung metastasis without affecting tumor growth or proliferation. At a dose of 20 mg/kg, dHG-5 prolonged activated partial thromboplastin time (APTT) from 23.5 ± 1.85 s to 30.4 ± 3.36 s, effectively reversing hypercoagulability in tumor-bearing mice. Compared to lowmolecular- weight heparin, dHG-5 selectively prolonged APTT with negligible effects on prothrombin time and thrombin time.

Discussion: The findings highlighted the dual-action mechanism of dHG-5, namely inhibiting heparanase and selectively targeting the intrinsic coagulation pathway. This selective action minimized bleeding risk, a common issue with traditional anticoagulants. However, this study focused on a single cancer type and the use of a mouse model, which may not fully represent human pathophysiology. We would explore dHG-5's effects across different cancer types and investigate its potential synergistic effects with existing cancer therapies in the future.

Conclusion: dHG-5 suppressed metastasis and hypercoagulability through heparanase inhibition and selective action on the intrinsic coagulation pathway. These findings highlight dHG-5 as a promising dual-action therapeutic candidate for managing metastasis and cancer-associated thrombosis, offering a safer alternative to traditional anticoagulants.