Ascidian dermatan sulfates attenuate metastasis, inflammation and thrombosis by inhibition of P‐selectin

Abstract

To cite this article: Kozlowski EO, Pavao MSG, Borsig L. Ascidian dermatan sulfates attenuate metastasis, inflammation and thrombosis by inhibition of P-selectin. J Thromb Haemost 2011; 9: 1807-15.See also Zacharski LR. Controlling cancer growth from within the blood coagulation mechanism. This issue, pp 1804-6.Summary. Background: Cancer-associated thrombosis and enduring inflammation are strongly associated with cancer progression and metastasis. Heparin is the mostly clinically used anticoagulant/antithrombotic drug, and has recently been shown to exhibit antimetastatic and anti-inflammatory activities that are linked to inhibition of P-selectin and/or L-selectin. P-selectin-mediated platelet-tumor cell and tumor cell-endothelium interactions facilitate the initial steps of metastasis. Objectives and Methods: The aim of the present study was to determine the capacity of dermatan sulfates to inhibit P-selectin and to test their potential to affect thrombosis, inflammation and metastasis in respective experimental mouse models. Results: Two dermatan sulfates isolated from the ascidians Styela plicata and Phallusia nigra, composed of the same disaccharide core structure (IdoA2-GalNAc) n , but sulfated at carbon 4 or 6 of the GalNAc, respectively, have opposed heparin cofactor II (HCII) activities and are potent inhibitors of P-selectin. The ascidian dermatan sulfates effectively attenuated metastasis of both MC-38 colon carcinoma and B16-BL6 melanoma cells and the infiltration of inflammatory cells in a thioglycollate peritonitis mouse model. Moreover, both glycosaminoglycans reduced thrombus size in an FeCl 3 -induced arterial thrombosis model, irrespective of their HCII activities. The analysis of arterial thrombi demonstrated markedly reduced platelet deposition after dermatan sulfate treatment, suggesting that the glycosaminoglycan inhibited P-selectin and thereby the binding of activated platelets during thrombus formation. Conclusions: Collectively, these findings provide evidence that specific inhibition of P-selectin represents a potential therapeutic target in thrombosis, inflammation and metastasis, and that ascidian dermatan sulfates may serve as antiselectin agents.

Selective Toxicity of Persian Gulf Sea Squirt (Phallusia nigra) Extract on Isolated Mitochondria Obtained from Liver Hepatocytes of Hepatocellular Carcinoma Induced Rat

“…The dermatan sulfates can significantly decrease metastasis of MC-38 colon carcinoma and B16-BL6 melanoma cells. In addition, a decrease in the size of thrombus in arterial thrombosis model has been observed (28). This compound has shown to inhibit P-selectin and bind activated platelets during thrombus formation and also, serves as a potential therapeutic product in thrombosis, inflammation, and metastasis (28).…”

“…These compounds contain heparin cofactor II (HCII) and have shown to be potent inhibitors of Pselectin (28). The dermatan sulfates can significantly decrease metastasis of MC-38 colon carcinoma and B16-BL6 melanoma cells.…”

“…It has been reported that apoptosis induced by marine species could justify development of non-cytotoxic anticancer treatments, novel apoptosis inducing drug candidates, and effective targeted cancer therapies. In order to reach the given objectives, marine animal bioactive compounds are considered a promising source of new anticancer drugs (28).…”

Antiplatelet Drugs in Coronary Artery Disease

“…However, due to headache, palpitations, and diarrhea, withdrawal of cilostazol approximated 15% [58,59]. Further antiplatelet strategies including blockade of inflammatory substances such as p selectin [60] or collagen receptors [61] are currently under clinical development. An accurate evaluation of the balance between the anti-ischemic effect and the hemorrhagic risk of these new drugs is highly warranted.…”

Role of P‑selectin in thromboembolic events in patients with cancer

“…However, in certain situations, such as in cases of surgery, acute myocardial infarction and septicemia, the D-dimer value may be shown to be reduced, as occurs in patients with cancer (22,23). P-selectin is a glycoprotein present in the endothelium and platelets (24,25) that, through the mediation of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), binds to leukocytes, primarily to neutrophils (26), with the function of facilitating the interaction (adhesion) of leukocytes with the endothelium or with platelets (27), besides exerting different roles in various stages of inflammation (28). A well-defined association exists between elevated serum levels of P-selectin and thrombosis (29).…”