The non-anticoagulant promise of heparin and its mimetics

The non-anticoagulant promise of heparin and its mimetics

Available online at www.sciencedirect.com ScienceDirect The non-anticoagulant promise of heparin and its mimetics Barbara Mulloy Heparin, the widely ...

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Available online at www.sciencedirect.com

ScienceDirect The non-anticoagulant promise of heparin and its mimetics Barbara Mulloy Heparin, the widely used anticoagulant and antithrombotic polysaccharide, has other potential therapeutic uses that arise from its similarity to heparan sulfate. This review provides a brief overview of the most recent developments in this field, paying particular respect to pulmonary and respiratory pharmacology. It has often been said that heparin, with its mimetics and derivatives, shows great promise in the treatment of inflammatory, infectious, and malignant conditions. Difficulties are encountered, however, in translating this promise into worthwhile treatment strategies for patients in some conditions. Several clinical trials of low molecular weight heparins as adjuvant therapy to standard treatment of lung cancers have recently provided no evidence to support the supposed beneficial effects of low molecular weight heparin. Address Institute of Pharmaceutical Science, King’s College London, 150 Stamford Street, London, SE1 9NH, UK

interact with many growth factors, morphogens, cytokines, chemokines and complement factors [2], variously potentiating or inhibiting their action, stabilizing their structures, encouraging the formation of protein multimers or acting as cell-surface co-receptors. In addition, HS is a selectin ligand, influencing the tethering and extravasation of leukocytes [3]. Taken all together, heparin can be thought of as a heparan sulfate mimetic, particularly in the context of the inflammatory response common to many lung disorders. Exogenous soluble heparin can, therefore, compete with cell-surface HS for protein ligands, disrupting such processes as chemotaxis and growth factor receptor function [4] and so having an anti-inflammatory effect. Heparin can also act as a substrate and inhibitor for the HS degrading enzyme heparanase, important in inflammation and metastasis. Heparanase has both enzymatic and non-enzymatic functions involved in tumor biology and inflammation and is a well-recognized target molecule in development of antitumor and anti-inflammatory therapies [5].

Corresponding author: Mulloy, Barbara ([email protected])

Current Opinion in Pharmacology 2019, 46:50–54 This review comes from a themed issue on Respiratory Edited by Simon Pitchford

https://doi.org/10.1016/j.coph.2019.03.009 1471-4892/ã 2018 Elsevier Ltd. All rights reserved.

Introduction Heparin is an unusual drug. It is a heterogenous, polydisperse sulphated polysaccharide extracted from hog or cattle intestinal mucous lining, where it is found in the granules of mast cells [1]. It is a member of the class of anionic polysaccharides known as glycosaminoglycans (GAGs). Heparin is a potent anticoagulant, and is used in the treatment and prophylaxis of thrombosis in millions of patients each year. Besides the interactions with the coagulation system that underlie the clinical use of heparin, other biological effects of heparin might be developed for therapeutic application. There are strong structural similarities between heparin and the ubiquitous cell surface and extracellular matrix polysaccharide heparan sulfate (HS). Heparin and HS Current Opinion in Pharmacology 2019, 46:50–54

It may not be desirable for a drug intended for a specific anti-inflammatory or anti-cancer use to express a wide range of other physiological effects, such as the potent anticoagulant activity of heparin, which might lead to side-effects such as bleeding [6] and so restrict the safe dose range (though some routes of administration, such as inhalation, offer much reduced side effects [7]). The anticoagulant activity of heparin is dominated by one particular structural feature, a pentasaccharide sequence with high affinity for antithrombin, and this sequence has been developed into a synthetic drug [8]. If affinity for other proteins than antithrombin also depended on similarly specific sequences, the same strategy of developing a synthetic heparin fragment could be applied to other activities of heparin, but the situation is more complex than that. Heparin is a highly anionic polymer, and it may well be the case that some of its properties depend simply on its size and strong negative charge. Another possibility lies between the extremes; a heparin-binding protein may recognize a structural motif common to several monosaccharide sequences [9].

Modified heparins and heparin mimetics The structure of heparin can be tailored in the laboratory to emphasize certain aspects of its spectrum of activities and to suppress others. For example, the capacity of heparin to prevent coagulation can be an asset or a dangerous sideeffect depending on the intended use of the drug. Removal of the antithrombin binding motif by chemical methods, or design of synthetic and semi-synthetic heparins without it, can provide heparin-like preparations with little or no www.sciencedirect.com

Non-anticoagulant heparins Mulloy 51

Figure 1

Galectin-III binding, HMGB1 release inhibitors

Heparanase inhibitors, anti-metastatic agents

Trials as adjuvant therapy in lung cancers

Roneparstat, necuparanib Desulfated heparins

Low molecular weight heparin Glycol-split

Partial desulfation

Natural products Fucans, galactans from marine sources

Selectin ligands, anti-metastatic agents

HEPARIN DERIVATIVES

HEPARIN MIMETICS

Partial depolymerization

Synthetics HS-mimetic glycopolymer, synthetic oligosaccharides

Semi-synthetics Pentosan polysulfate

Heparanase inhibitors

Potential treatment for rhinitis, arthritis, transmissible encephalopathies

Current Opinion in Pharmacology

A simplified overview of some heparin-related compounds developed for use in non-anticoagulant applications. In the upper half of the diagram, heparin itself can be altered by desulfation, periodate treatment followed by reduction (‘glycol-split’) or depolymerization to give heparin derivatives with altered biological activity (in grey text). In the lower half of the diagram, heparin mimetics not made directly from heparin can be natural products, semi-synthetics such as chemically sulfated polysaccharides, and artificial glycopolymers designed specifically as enzyme inhibitors. Examples of the useful properties of these preparations are in green, all taken from the main text of this article.

antithrombin-mediated anticoagulant activity [10]. There exist several modified heparins and oligosaccharide or polysaccharide heparin mimetics, some prepared from natural products and others wholly or partly synthetic [3,10,11] (Figure 1). Heparins can also be modified or formulated to allow administration by non-conventional routes; though effective orally active heparin derivatives are unusual [12,13], nebulized heparin, administered by inhalation, is a promising strategy to achieve localized treatment of lung conditions [14]. A variety of similar formulations, including microspheres, nanoparticles and liposomes, are also being devised for anti-tumor applications using combinations such as heparin/usnic acid [15] and heparin/doxorubicin [16]. Heparin-containing nanoparticles have been designed to deliver siRNA to lung cancers [17]. Topical nasal administration of the semi-synthetic heparin mimetic pentosan polysulfate alleviated influx of nasal lumen leukocytes and extravasation of plasma in allergic rhinitis, possibly through interaction with Th2 cytokines IL-4, IL-5, and IL-13 [18]. The anti-inflammatory action of pentosan polysulfate may also lie behind its apparent effectiveness as an anti-arthritic agent [19]. Pentosan polysulfate has also been identified as a potential treatment for transmissible encephalopathies [20], illustrating the considerable range of systems in which heparin mimetics can plausibly make a contribution.

Heparin and its mimetics in lung disorders Inflammatory disease

The use of heparin and its derivatives in the treatment of asthma and chronic obstructive pulmonary disease (COPD) has recently been reviewed [7], listing good results in several small trials that encourage the use of inhaled heparin as an add-on therapy for COPD. These www.sciencedirect.com

include a pilot study indicating that inhaled, nebulized heparin induces clinically significant improvement in lung function in COPD patients [21] without any effects on systemic blood coagulation. An oxidized, sulfated non-anticoagulant ultra-low molecular weight heparin (uLMWH) preparation has been developed that was able to ameliorate a number of asthma symptoms in a mouse model, possibly through a Th-cytokine mechanism involving the blocking of IL-4 mediated signal transduction [22]. Several recent studies have identified heparin as an effective inhibitor of the high-mobility group box-1 (HMGB1). This is a pro-inflammatory factor involved in acute lung injury; it is a chromatin protein that when secreted by immune cells acts as a cytokine, inducing disruption in the barrier function of pulmonary microvascular endothelial cells [23]. Heparin can inhibit this disruption and, therefore, potentially restore vascular endothelial barrier integrity. HMGB1A is a peptide antagonist to HMBG1, and when complexed with heparin reduced pro-inflammatory cytokines more effectively than either component alone in a mouse lung injury model [24]. A partially desulfated heparin can inhibit the secretion of HMGB1 from murine macrophage cells, probably by inhibition of HMGB1 acetylation in the cytoplasm [25]. The anti-inflammatory effect of unfractionated heparin on human alveolar macrophages, alveolar type II cells, and fibroblasts that had been injured with LPS, have led to a hypothesis that local pulmonary administration of heparin through nebulization may be able to reduce inflammation in the lung in the treatment of Acute Respiratory Distress Syndrome (ARDS) [26]. Nebulized heparin was able to reduce lung inflammation in a model of acute lung injury through reducing both procoagulant and proinflammatory factors [27].In contrast, a systematic review of preclinical Current Opinion in Pharmacology 2019, 46:50–54

52 Respiratory

and clinical studies of nebulized anticoagulants in critically ill lung injury patients has concluded that the evidence for efficacy of nebulized heparin remains limited, with contradictory results from the few, not always satisfactory, human trials available [28]. Infectious disease

The innate immune response to infection in the lung is modulated by proteoglycans [29], the protein-based glycoconjugates that carry HS and other GAGs. Heparin, when introduced exogenously, has anti-inflammatory properties [1] that underpin the rationale for its use in both direct and indirect effects of infection. For example, low molecular weight heparin (LMWH) treatment has significantly reduced the levels of inflammatory proteins and neutrophil sequestration in a rat sepsis model [30]. Long-term chronic infection with Pseudomonas aeruginosa in murine lungs induces structural changes in lung HS, and two forms of non-anticoagulant heparin (glycol-split and N-acetylated heparins) were effective in both dampening the inflammatory response to infection and reducing bacterial burden [31]. GAGs are involved in the adherence of many pathogens to the cell surface, as has recently been shown for interactions between Gram positive and Gram negative pathogenic bacteria and the lung cell lines A549 and MRC5 [32]. HS chains attached to the cell-surface proteoglycan syndecan-4 play a part in the attachment of mycobacterial adhesins in tuberculosis, leading to attachment and internalization of the pathogen [33]. The involvement of HS in host–pathogen interactions suggests that the use of heparin to compete with HS and so interfere with the binding of bacterial pathogens to host cells might be a useful treatment strategy in lung infections, where the inhalation route may be able to deliver an appropriate concentration of heparin [34]. Low-dose nebulized heparin, however, was found ineffective as a prophylactic agent against ventilator-associated pneumonia [35]. Cancer Basic and pre-clinical studies

Why should heparin have a beneficial effect on cancer patients, other than through prevention and treatment of thrombosis? In its role as a HS mimetic, heparin can inhibit most physiological processes involved in the development of cancer [36]. A recent concise review summarizes the role of HS in cancer initiation and progression [37] and identifies the development of therapeutic strategies based on small molecule modulators of HS biosynthesis and immunotherapeutic approaches as well the use of HS mimetics. In particular, heparin, as an inhibitor of P-selectin, heparanase, and tumor angiogenesis, is expected to have an antimetastatic effect, and has been suggested as a useful Current Opinion in Pharmacology 2019, 46:50–54

adjuvant to standard treatment [10]. The ability to inhibit metastasis is common to many sulphated polysaccharides, whether heparin-like [38] or not, such as echinoderm fucans and galactans [39] and is not related to anticoagulant activity; recent developments in the design of synthetic glycopolymer anti-metastatic heparanase inhibitors have shown promise in pre-clinical tests in breast cancer [40]. An unusual oral anti-angiogenic agent has been devised, in which heparin is conjugated with taurocholic acid and a tetradeoxycholic acid so that the compound can be absorbed by the apical sodium-dependent bile acid transporter (ASBT)-mediated pathway [13], and, therefore, has much increased oral bioavailability. This conjugate reduced tumor volume in a xenograft model of human A549 lung cancer cells. Heparin can be a substrate for heparanase but is more often regarded as an inhibitor. Some heparin derivatives are effective heparanase inhibitors, such as the N-acetylated, glycolsplit non-anticoagulant heparin derivative roneparstat [41], or u-LMWH heparins prepared by ultrasonic-assisted radical hydrolysis [42]. These derivatives have reduced anticoagulant activity as compared with the heparin parent. A detailed study of synthetic trisaccharides has elucidated the conformational changes introduced by glycol splitting that increase the affinity of roneparstat and necuparanib for heparanase [43]. Heparanase is a particularly good target for mesothelioma, in which therapeutic options are limited. Heparanase inhibitors based on a sulfated glycan structure were found to be as effective as cisplatin in restraining the growth of mesothelioma tumor xenografts [44]. Also promising are pre-clinical studies for synovial sarcoma treatment with a combination of an insulin-like growth factor 1 receptor/ insulin receptor inhibitor and a supersulfated LMWH, in which the combination strategy strongly enhanced antitumor and metastatic effects as compared with the tyrosine kinase inhibitor alone [45]. A further possible mechanism for the inhibition of metastasis by heparin is interaction with galectin-3, a glycan-binding protein upregulated in many cancers. Circulating galectin-3 promotes metastatic spread. A series of partially desulfated heparin derivatives were found to inhibit both galectin-3 binding and galectin-3-mediated metastasis [46]. Clinical trials

The substantial FRAGMATIC Phase 3 trial [47] involved over 2000 patients with a newly diagnosed lung cancer of any stage or histology, adding daily subcutaneous 5000 IU dalteparin to standard treatment. The primary endpoint of overall survival was not altered by dalteparin treatment, nor was the 1-year survival rate. The potential antithrombotic benefit of heparin was noted: there was a significant reduction in VTE in the LMWH arm of the trial. This was, however, associated with increased bleeding risk, and the authors recommend that some strategy be devised to target those patients particularly at risk of VTE. www.sciencedirect.com

Non-anticoagulant heparins Mulloy 53

Furthermore, the results of two clinical trials published in 2018 do not encourage optimism about the use of LMWH in lung cancer. The RASTEN Phase III trial [6] investigated the effects of a supraprophylactic subcutaneous dose of enoxaparin (1 mg/kg), in addition to standard treatment, on survival of small cell lung cancer patients. No significant difference in overall survival times was found between enoxaparin treated and control patients. In addition, a Phase 3 trial in completely resected non-small cell lung cancer patients has recently been reported, in which subcutaneous tinzaparin at 100 IU/kg daily for 12 weeks failed to have an impact on survival of patients after five years [48]. These are all disappointingly negative results, as was the failure of the non-anticoagulant heparin derivative necuparanib in Phase 2 pancreatic cancer trials [49] in spite of good preclinical indicators [50].

3.

Farrugia BL, Lord MS, Melrose J, Whitelock JM: The role of heparan sulfate in inflammation, and the development of biomimetics as anti-inflammatory strategies. J Histochem Cytochem 2018, 66:321-336.

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Shute J: Glycosaminoglycan and chemokine/growth factor interactions. Handb Expl Pharmacol 2012, 207:307-324.

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Pisano C, Vlodavsky I, Ilan N, Zunino F: The potential of heparanase as a therapeutic target in cancer. Biochem Pharmacol 2014, 89:12-19.

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Ek L, Gezelius E, Bergman B, Bendahl PO, Anderson H, Sundberg J, Wallberg M, Falkmer U, Verma S, Belting M, Swedish Lung Cancer Study Group (SLUSG): Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial. Ann Oncol 2018, 29:398-404.

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Shute JK, Puxeddu E, Calzetta L: Therapeutic use of heparin and derivatives beyond anticoagulation in patients with bronchial asthma or COPD. Curr Opin Pharmacol 2018, 40:39-45. An authoritative, specialized review with particular emphasis on the potential of inhaled heparin in the treatment of asthma and COPD. 8.

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Conclusions Recent explorations of heparin mimetics with reduced anticoagulant action by comparison with native heparin have continued to show great promise in preclinical studies, in the treatment of a wide variety of airway disorders, from allergic rhinitis to aggressively metastatic malignant tumors. It is unclear, however, why the strong pre-clinical promise of heparin treatment in cancer has not been reflected in clinical trials. The simple addition of heparin to other cancer treatments, as the conceptually ‘easy option’ HS mimetic, may be oversimplistic, and issues of bioavailability might arise given the subcutaneous route of administration and the limited doses necessary to avoid coagulation related side effects. These results are in contrast with the largely positive outcomes for trials of inhaled heparin in the treatment of inflammatory lung disease listed in a recent article in this journal [7]. We await with interest results of current and future clinical studies on the expanding range of new HS mimetic structures and formulations.

Funding Preparation of this article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest statement Nothing declared.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

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