Inhibitory effect of non-anticoagulant heparin (S-NACH) on pancreatic cancer cell adhesion and metastasis in human umbilical cord vessel segment and in mouse model

Abstract

Metastasis is the most devastating aspect of cancer and it is the main cause of morbidity and mortality in cancer patients. Tumor cell adhesion to the vascular endothelial cell lining is an important step in metastatic progression and is prompted by platelets. Mucin 1 is over-expressed and aberrantly glycosylated in more than 60% of pancreatic ductal adeno-carcinomas, which mediate adhesion of pancreatic cancer cells to platelets via P-selectin. The anticoagulant low molecular weight heparins (LMWHs), which are commonly used in venous Thromboprophylaxis and treatment, appear to have an effect on cancer survival. The aim of this study is to investigate the effect of platelets on human pancreatic cancer MPanc96 cell adhesion to the endothelial cell vessel wall, and to examine the effect of heparin derivatives on MPanc96 adhesion using a novel, in vitro model of human umbilical cord vein. The modified heparin S-NACH (sulfated non-anticoagulant heparin), which is devoid of antithrombin (AT) binding and devoid of inhibition of systemic AT-dependent coagulation factors such as factor Xa and IIa, and the LMWH tinzaparin both potently reduced adhesion and invasion of fluorescence-labeled MPanc96 cancer cells to the endothelial layer of umbilical cord vein in a dose-dependent manner. S-NACH effectively inhibited P-selectin mediated MPanc96 cell adhesion, and inhibited cell adhesion and invasion similar to tinzaparin, indicating that systemic anticoagulation is not a necessary component for heparin attenuation of cancer cell adhesion, invasion, and metastasis. Also, S-NACH and tinzaparin versus unfractionated heparin, heparin derivatives enoxaparin, deltaparin, fraxiparin, and fondaparinux were evaluated for their effect on platelet-cancer cell adhesion. An in vivo anti-metastatic S-NACH-treated nude mouse model of MPanc96 pancreatic cancer cell metastasis demonstrated potent anti-metastasis efficacy as evidenced by IVIS imaging and histological staining.

Anti-metastasis efficacy and safety of non-anticoagulant heparin derivative versus low molecular weight heparin in surgical pancreatic cancer models

“…It was shown that the effect of S-NACH in inhibiting metastasis is not related to the heparin anticoagulant property as reported from our laboratory, and by others (14,15,24). These results indicate that the beneficial use of LMWH and its derivatives is not due to its anticoagulant activity.…”

“…Xenogen IVIS Living Image software (Caliper Life Sciences, version 3.2) was used to quantify non-saturated bioluminescence in regions of interest (ROI). Bioluminescence was quantified as photons/second for each ROI (15).…”

“…Hence, NACH is expected to have the same anti-metastatic effect as LMWH because it carries all properties of heparin except the anticoagulant activity. In our laboratory we developed a novel sulfated form of NACH, named S-NACH, and it was found to be effective and safe in a mouse model of tumor growth and tumor angiogenesis (15).…”

Modulation of Sickle Red Blood Cell Adhesion and its Associated Changes in Biomarkers by Sulfated Nonanticoagulant Heparin Derivative

“…21,22 We also showed that S-NACH can interfere with the P-selectin-dependent binding of cancer cells to endothelial cells, both in vitro and in vivo. 23 In this study, we test the hypothesis that S-NACH via its antithrombotic effects and by interference with the Pselectin-dependent binding of sickled RBCs to endothelial cells will decrease the adhesion of sickle RBCs to the endothelial cells. By in vitro static adhesion assay, we show here for the first time that S-NACH decreases the increased adhesion of sickle RBCs to endothelial cells.…”

Advanced Pancreatic Cancer: Flourishing Novel Approaches in the Era of Biological Therapy

“…In vitro, a heparin-derived agent devoid of anticoagulant effect has been found to inhibit tumor growth via disruption of heparanase activity. Nonanticoagulant heparin S-NACH was also found to inhibit pancreatic cancer cell adhesion and metastasis [79]. In an animal study, heparin derivate showed anticancer and antiangiogenic effects [80].…”