Periodate-treated, non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) affects angiogenesis and inhibits subcutaneous induced tumour growth and metastasis to the lung

Abstract

Periodate-treated, non-anticoagulant heparin-carrying polystyrene consists of about ten periodate-oxidized, alkaline-degraded low molecular weight-heparin chains linked to a polystyrene core and has a markedly lower anti-coagulant activity than heparin. In this study, we evaluated the effect of non-anticoagulant heparin-carrying polystyrene on tumour growth and metastasis. Non-anticoagulant heparin-carrying polystyrene has a higher activity to inhibit vascular endothelial growth factor-165-, fibroblast growth factor-2-or hepatocyte growth factor-induced human microvascular endothelial cell growth than heparin, ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin, which is probably due to the heparin-clustering effect of non-anticoagulant heparin-carrying polystyrene. Non-anticoagulant heparin-carrying polystyrene inhibited human microvascular endothelial cell, B16 melanoma and Lewis lung cancer cell adhesion to Matrigel-coated plates. Non-anticoagulant heparin-carrying polystyrene also showed strong inhibitory activities in the tubular formation of endothelial cells on Matrigel and B16-melanoma and Lewis lung cancer cell invasion in a Matrigel-coated chamber assay. In vivo studies showed that growth of subcutaneous induced tumours and lung metastasis of B16-melanoma and Lewis lung cancer cells were more effectively inhibited by non-anticoagulant heparin-carrying polystyrene than ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin. Furthermore, non-anticoagulant heparin-carrying polystyrene markedly reduced the number of CD34-positive vessels in subcutaneous Lewis lung cancer tumours, indicating a strong inhibition of angiogenesis. These results suggest that non-anticoagulant heparin-carrying polystyrene has an inhibitory activity on angiogenesis and tumour invasion and may be very useful in cancer therapy.

Antimetastatic activities of heparins and modified heparins. Experimental evidence

“…The use of non-anticoagulant heparin derivatives in a number of animal models resulted in attenuation of metastasis, further demonstrating that the antimetastatic activity of heparins is independent of anticoagulation [14,16,17,28,43,44]. The pentasaccharide fondaparinux, an excellent anticoagulant that potentiates antithrombin III, had no affect on metastasis at clinically tolerable levels [26,31].…”

miR-200b Targets Ets-1 and Is Down-regulated by Hypoxia to Induce Angiogenic Response of Endothelial Cells

“…For the in vitro angiogenesis assay, cells were plated out after transfection or treatment and seeded on a Matrigel pre-coated 4-well plates at 5 ϫ 10 4 cells/well. The angiogenic property was assessed 8 h after seeding as described previously (18), and the tube length was measured using the AxioVision Rel 4.6 software (Zeiss). For the cell migration assay, cells were seeded at the confluent monolayer on a 4-well plate.…”

Low-Anticoagulant Heparins in the Treatment of Metastasis

“…Of the available low anticoagulant heparin derivatives (Casu et al, 2008;Fryer et al, 1997;Kragh & Loechel, 2005;Lapierre et al, 1996;Ono et al, 2002;Rao et al, 2010;Stevenson et al, 2007;Wang et al, 2002;Yoshitomi et al, 2004), only ODSH has been proven safe from major adverse events in humans ) data on file with FDA) and only ODSH is free from the potential to induce HIT . The concept that P-selectin is the key molecule in metastasis is based on the attenuation of metastasis in animal models.…”

“…However, shortly after its initial discovery, it was reported that heparin had an inhibitory effect on tumor growth in animals (Goerner, 1930). This initial observation led to intensive investigation with regard to heparin's anticancer and anti-metastatic properties (Casu et al, 2010;Casu et al, 2008;Hettiarachchi et al, 1999;Kragh & Loechel, 2005;Lapierre et al, 1996;Lever & Page, 2002;Ono et al, 2002;Ornstein & Zacharski, 1999;Smorenburg et al, 1996;Stevenson et al, 2005;Stevenson et al, 2007;Vlodavsky et al, 2006;Yip et al, 2006;Yoshitomi et al, 2004). The usefulness of heparin as an anticancer drug has been hindered by its anticoagulant effect at therapeutic doses required to inhibit cancer growth and spread.…”