Glycosaminoglycans in Acncer Therapy: History
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Subjects: Biochemistry & Molecular Biology
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Dragana Nikitovic

The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM). Glycosaminoglycans (GAGs), natural biomacromolecules, essential ECM, and cell membrane components are extensively altered in cancer tissues. During disease progression, the GAG fine structure changes in a manner associated with disease evolution. Thus, changes in the GAG sulfation pattern are immediately correlated to malignant transformation. Their molecular weight, distribution, composition, and fine modifications, including sulfation, exhibit distinct alterations during cancer development. GAGs and GAG-based molecules, due to their unique properties, are suggested as promising effectors for anticancer therapy. Considering their participation in tumorigenesis, their utilization in drug development has been the focus of both industry and academic research efforts. These efforts have been developing in two main directions; (i) utilizing GAGs as targets of therapeutic strategies and (ii) employing GAGs specificity and excellent physicochemical properties for targeted delivery of cancer therapeutics.

  • glycosaminoglycans
  • cancer
  • cancer therapy
  • hyaluronan
  • heparan sulfate
  • heparin
  • chondroitin sulfate
  • drug carriers
  • nanomaterial
  • therapy targets

1. Introduction

The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM) [1]. The ECM is a significant component of the TME with a vital role in cancer’s pathogenesis [2][3]. It is well established that TME plays an essential role in tumorigenesis. Indeed, tumor growth and metastasis steps, e.g., primary lesion development, intravasation, extravasation, and metastasis to anatomically distant sites, are executed via the discrete interplay of the tumor cells with their microenvironment [4]. Glycosaminoglycans (GAGs), natural biomacromolecules, and essential ECM and cell membrane components are extensively altered in cancer tissues [5]. Indeed, these heteropolysaccharides vital in supporting homeostasis have also been established to participate in inflammatory, fibrotic, and pro-tumorigenic processes [6][7][8][9]. Both free GAGs and GAGs bound into the protein cores of proteoglycans- (PG) are crucial mediators of cellular and ECM microenvironments, with the ability to specifically bind and regulate the function of ligands and receptors crucial to cancer genesis [4][10][11].

Structurally, GAGs are linear, long-chained polysaccharides consisting of repeating disaccharide units linked by glycosidic bonds. These building blocks are composed of N-acetylated hexosamine and uronic acid. The type of the disaccharide repeating unit and its modifications, including discrete sulfation patterns, allows the classification of GAGs into specific categories, e.g., chondroitin sulfate (CS)/dermatan sulfate (DS), heparin (Hep)/heparan sulfate (HS), keratan sulfate (KS) and hyaluronan (HA) [12][13][14][15]. KS chains contain galactose instead of uronic acid in their disaccharide building blocks [15]. CS/DS, HS/Hep, and KS chains are covalently bound into the protein cores of proteoglycans [6]. On the other hand, the non-sulfated GAG HA is not bound into the proteoglycan core but is secreted to the ECM of almost all tissues [13].

Bound GAGs are initially synthesized on core proteins at the Golgi lumen. Their glucuronic acid—N-acetylglucosamine/N-acetylgalactosamine(GlcA-GlcNAc/GalNAc) or, in the case of KS, galactose-N-acetylglucosamine (Gal-GlcNAc) repeating units are subjected to significant structural modification, including sulfation and in the case of HS/CS epimerization at the Golgi apparatus. Moreover, the desulfation of HS chains is performed at the cell membrane compartment [16]. The fine modifications result in an astonishing number of divergent GAG structures.

The GAG fine modifications define, to no small degree, the specificity of their binding with proteins. Notably, GAGs have been shown to interact with more than 500 proteins [17]. The interactions of GAGs with membrane receptors, ECM proteins, chemokines, and cytokines, as well as enzymes and enzyme inhibitors, are crucial in both development and homeostasis [18][19]. Likewise, GAGs’ interactions with the above, both soluble and insoluble ligands, play a vital role in various diseases, including cancer [20]. By modulating numerous signaling pathways, GAGs exert distinct effects on cancer cells’ functions, cancer stroma interactions, and cancer-associated inflammation, thus regulating essential processes for tumor progression and metastasis [1][4][6][21].

During disease progression, the GAG fine structure changes in a manner associated with disease evolution. Thus, changes in the GAG sulfation pattern are immediately correlated to malignant transformation [22]. Their molecular weight, distribution, composition, and subtle modifications, including sulfation, exhibit distinct alterations during cancer development [23][24]. Thus, most tumor types exhibit increased CS content with an increase in the 6-O-sulfated and/or unsulfated disaccharide content and a decrease in the 4-O-sulfation level due to changes in relevant enzyme activities [23][24]. Likewise, an aberrant HS sulfation pattern has been correlated to tumorigenesis. It was shown that the N-sulfation of GlcNresidues in specific domains along the HS chain facilitates tumor angiogenesis [25]. The expression of HS 6O-sulphated disaccharide content was shown to be increased during chondrosarcoma [26] and colon carcinoma progression [27].

GAGs and GAG-based molecules, due to their unique properties, are suggested as promising effectors for anticancer therapy [28]. Considering their participation in tumorigenesis, their utilization in drug development has been the focus of both industry and academic research efforts [29]. These efforts have been developing in two main directions; (i) utilizing GAGs as targets of therapeutic strategies and (ii) employing GAGs exquisite specificity and excellent physicochemical properties for targeted delivery of cancer therapeutics.

2. Focus on GAGs’ Structure and Roles

GAG polymers are assembled through several consecutive steps with different enzymes’ involvement at each separate stage. Sulfated GAGs are synthesized by specific enzymes in the cell’s Golgi apparatus, whereas HA is synthesized by transmembrane proteins called HA synthases (HASs). While HA is not linked to a protein and is produced from its reducing end, the sulfated GAGs are built up from the non-reducing end and synthesized as side chains attached to a protein core of PGs [5].

In the case of KS, GlcA is replaced by GalN. Henceforth, the growing GAG chain’s modifications, e.g., deacetylation/N-sulfation and epimerization of GlcA to IdoA followed by O-sulfation, are performed [30][31]. Therefore, the individualized functionalization of GAGs results in their unique structures. Indeed, distinct sulfation patterns have been identified at the disaccharide unit’s functionalization sites, hexosamine, and IdoA components, facilitating great complexity and structural diversity [32][33].

Different variations in the expressions/activities of enzymes involved in GAG synthesis have been described. One example is that the levels of exostoses (multiple)-like 1 (EXTL1) and CS N-acetylgalactosaminyltransferase 1 (CSGalNAcT-1), which participate in the production of HS and CS, respectively, were shown to exhibit an inverse ratio of expression. The inverse expressions identified in the process of B-cell differentiation have been suggested to act as a switch enabling either CS or HS synthesis observed during these cell differentiations [34].

2.1. Heparin and Heparan Sulfate

Both Hep and HS chains are synthesized as a modification of a PG protein core, sharing a biosynthetic scheme but exhibiting some disparities [35][36]. Thus, initially, the sequential addition of four sugar residues by different glycosyltransferases will give rise to the linker tetrasaccharide (for Hep/HSXyl-Gal-Gal-GlcA) connected to the core protein’s serine residue as a linker region [37]. Notably, the linkage region also serves as a primer for the initiation of the CS chains biosynthesis. In the case of HS, the members of the EXTL family of glycosyltransferases trigger chain creation by transferring an N-acetylglucosamine (GlcNAc), whereas in the case of CS chains, a β-N-acetylgalactosamine (β-GalNAc) residue is attached to the linkage primer by a CSGalNAc-transferase [37]. Polymerization of HS then takes place by the alternating addition of GlcAβ1,4 and GlcNAcα1,4 residues through the action of designated glycosyltransferases [38]. Modifications, such as N-deacetylation and N-sulfation of glucosamine, and O-sulfations are subsequently performed. The GlcA residues can, on some occasions, be epimerized to iduronic acid (IdoA)[35][36].

The two GAGs differ, as the main HS disaccharide unit comprises a GlcA and N-acetylated GlcN(GlcNAc). In contrast, the main Hep disaccharide consists of sulfated, at the carbon 2 IdoA(IdoA2S), and N-sulfated GlcN also sulfated at C6 (GlcNS6S). Due to the high Hep sulfation level, this GAG is characterized as a biomacromolecule with the highest negative charge density [39]. The functionalization with sulfate is uniformly distributed along the Hep chain, whereas HS chains exhibit alternatively exchanging regions of high sulfation with lower or non-sulfated sequences [40]. Indeed, Sulf-1 and Sulf-2, sulfatase enzymes, are active at the extracellular compartment and trim the 6-O-sulfates partially from HS, but do not affect Hep, which is not located at the cells’ membranes [41]. As a result, the Hep chain mainly comprises trisulfated disaccharides (80%) consisting of sulfated IdoA and sulfated GlcN.

The HS chains predominantly consist of disaccharide repeats comprised of GlcA and GlcNAc, with a much lower sulfation level [42]. Notably, the “fully sulfated” HS sequences, denominated as S domains, commonly exhibit the highest binding propensity to Hep/HS-binding proteins [43]. Indeed, the binding between proteins and HS/Hep is most commonly executed by charge–charge interactions between the proteins’ basic amino acids and the anionic sulfate and/or carboxylate [18][44]. The interaction between respective binding proteins and HS is likewise affected by the GAG heterogeneity and cationic association [19]. Moreover, posttranslational modifications, such as N-glycosylation, of the HS/Hep binding proteins can regulate ligand and HS/Hep binding as shown for the fibroblast growth factor receptor 1 [45]. Notably, its disaccharide unit’s extensive modifications render HS the most complex animal polysaccharide [19].

HS chains are synthesized by almost all mammalian cells in the forms of HSPG and are localized to the cell membrane (e.g., syndecans) and pericellular space/basement membranes (e.g., perlecan) or extracellular matrices. Despite the HS chain’s extensive functionalization, its fine structure is notably conserved in a given cell type [46][47]. HS’s composition varies both spatially and temporally during development and in a celltype-dependent manner. The involved regulating mechanisms remain poorly elucidated.

Significant changes occur in HS composition during carcinogenesis, and vitally, both tumor growth and tumor-dependent angiogenesis depend on HS growth factor interactions [48].

Hep is synthesized only in connective tissue-type mast cells or basophils [49]. The Hep chain is synthesized during the core protein modification of the PG, serglycin. Seglycine exhibits a small protein core but undergoes extensive glycosylation, resulting in a molecular weight up to 750 kDa [50]. The bound Hep chains’ molecular weight varies between 60 KDa and 75 kDa. These Hep chains are cleaved into 5–25 kDa fragments when mast cells and basophils are degranulated [51][52]. Mast cells release Hep by exocytosis upon binding specific antigens to the IgE antibodies attached to their cell-surface receptors [53]. However, Mast cell serglycin can also be decorated by other GAG chains, such as CS and DS [54].

Hep, however, can be uptaken by various cells, including endothelial cells, as the primary site for removing unfractionated Hep from the circulation is the liver sinus endothelial cells [55].

In mammalians, HS/Hep are enzymatically degraded by heparanase, a strict endo-β-glucuronidase [56].

2.2. Chondroitin Sulfate/Dermatan Sulfate

The CS chains consist of disaccharides comprising β(1-4) GlcA and β(1-3) GalNAc. The sulfation pattern of the GlcA and GalNAc determines the type of CS. Thus, CS-A is characterized by single sulfation at C4 of the GalNAc, whereas CS-C is determined by single sulfation at C6 of GlcA. Other functionalizations exist, as GalNAc can be sulfated at the carbon 4 and/or 6, whereas GlcA can also be sulfated at the C2 and/or C3 [57][58]. On the other hand, CS-B denominated similarly to DS, consisting of alternating GlcA or IdoA, which can be sulfated at C2, and GalNAc, which can be functionalized by sulfation at C4 or C6 [58]. Both CS and DS exhibit vast differences regarding chain length and MW, with the latter being in the 5–70 kDa range [59]. The prominent heterogeneity of the CS/DS chains is directly correlated to these GAGs’ biological roles [60][61].

An example is the altered functionalization of CS/DS in gastric cancer as the sulfation at C4 is downregulated, and sulfation at C6 increased in tumor cells compared to normal gastric cells. Additionally, the chain length of CS/DS and the GAG content of the PGs, decorin, and versican was decreased significantly.

2.3. Keratan Sulfate

The KS chains consist of disaccharides containing β(1-4) GlcNAc and β(1-3) Gal. This specific glycosidic binding results in a GAG chain formation, unique for its lack of a carboxyl group. KS’, binding into the protein core of PGs differs compared to HS/CS. Thus, corneal KS denominated as KS-I binds to an Asn in the core proteins through an N-linked complex, branched oligosaccharide. On the other hand, in cartilage, the KS chains denominated as KS-II utilize their N-Acetylgalactosamine (GalNAc) to establish an O-link with the Ser or Thr residues of the protein cores [62]. The type III KS (KS-III), initially identified in the brain tissue, links a mannose to a Ser residue of the protein core [63]. KS chains have a molecular weight ranging from 5–25 kD [64].

KS structure is mostly dependent on the tissue type as corneal KS-I exhibits longer chain length and a lower degree of sulfation than the cartilage KS-II. KS-III is mainly bound to PGs localized to the brain and nervous tissues [65][66]. The expression of KS is also deregulated in cancer. Indeed, it was suggested that KS’s aberrant expression could be utilized as a marker of pancreatic cancer progression and metastasis [67] and that highly sulfated KS is produced by malignant astrocytic tumors [68].

2.4. Hyaluronan

Transmembrane enzymes denominated HA synthases (HAS) produce HA chains. The three HAS isoforms, HAS1, HAS2, and HAS3, use cytoplasmic UDP-glucuronic acid and UDP-N-acetylglucosamine as substrates. Their active site is localized intracellularly, whereas the synthesized HA chain extrudes into the ECM [13]. This non-sulfated GAG is composed of repeating units of GlcNAc and GlcA combined by β-1.3 and β-1.4 linkages, with an average mass of 100–2000 kDa [13]. HAS1 and HAS2 synthesize a high molecular weight polymer, whereas HAS3 produces shorter chains (~2 × 106 Da vs. ~2 × 105 Da, respectively) [69]. HA’s biological information is translated to the length of its polymers and defines its effects [70]. The UDPsugar precursors and holistic cell metabolism responsible for producing HAS substrates critically regulate HASs activities [71]. HA-mediated effects are executed through various mechanisms that involve the binding of HA to surface receptors such as CD44 and RHAMM [72][73][74] and the internalization of HA through receptor-mediated endosomal pathways [75].

The human genome contains five active hyaluronidases (Hyals) (Hyal1–Hyal4 and PH-20) and the non-transcribed Hyal pseudogene (HyalP1). Hyal 2 and 3 exhibit degrading activity, exclusively for HA [76]. Some human Hyals exhibit degrees of CS-degrading activity. Thus, PH20 shows high activity for HA and low CS-degrading activity. On the other hand, Hyal1 degrades CS-A more swiftly than HA [77]. Hyal-4 is misnamed, as it shows specificity for CS and no ability to degrade HA [78].

Hyal1 is widely expressed and localized to lysosomes or trafficking vesicles [79]. However, Hyal 1 can also be secreted to the ECM by tumor cells [80]. Hyal1 is upregulated in many human cancers and has been correlated with tumorigenesis [81].

In contrast, Hyal2 is bound onto the cell membrane via a GPI anchor and is usually associated with lipid rafts [82], wherein, in common with CD44 and Hyal1, it promotes HA cellular uptake and endocytic internalization [75].

3. Targeting GAGs in Cancer—New Prospective

3.1. Targeting Heparan Sulfate/Heparin

HS, expressed by all mammalian cells in homeostasis [31], has been determined to be the most complex GAG [19]. This highly variable GAG is critical in cellular signaling and extensively remodeled during cancer progression. In its natural state, Hep is a heterogeneous mixture composed of polysaccharide chains that exhibit varying lengths and different sulfation patterns. Hep, compared to HS, is more homogeneous and its main function is storage. HS and Hep chains can establish specific interactions with various protein mediators regulating critical cellular signaling [18]. The affinity of HS/Hep chains to proteins such as growth factors seems to be significantly affected by their sulfation status and resulting electrostatic interactions [83][84][85]. Moreover, analysis by the polyelectrolyte theory demonstrated that the binding of FGF-2 to Hep is primarily accomplished through the more specific nonionic interactions, such as van der Waals packing and hydrogen bonding [86]. Therefore, inherent properties of the GAG chains need to be taken into account when designing novel drug carriers [83][84][85].

To date, more than 400 HS-binding proteins have been identified, including cytokines, growth factors, chemokines, ECM proteins, as well as enzymes and enzyme inhibitors [18]. Thus, the targeting of HS protein interactions is an essential developing therapy approach.

The strategies that have been examined for cancer-oriented therapy are based on (i) the utilization of GAG mimetics as competitive agents to block HS–protein interactions (ii) the utilization of enzymatic methods to cleave or modify HS to inhibit HS–protein interactions.

The utilization of unfractionated Hep and LMWHs is standard clinical practice for the protection against venous thromboembolism in cancer patients [87]. This clinical practice’s implementation has also demonstrated a beneficial effect of Hep on cancer patient survival discrete from its anticoagulant properties [88]. Indeed, Hep has now been recognized as a multifunctional drug [50]. Hep mimetics are commonly described as synthetic or semi-synthetic compounds that are anionic, usually highly sulfated, and structurally defined as distinct GAG analogs [89].

Research efforts focused on the synthesis of Hep derivatives with attenuated polypharmacy traits and anticoagulant activity, exhibiting enhanced potency and specificity while downregulating unwanted side effects, e.g., anticoagulation [89]. This approach has been facilitated by significant development in carbohydrate synthesis, including one-pot multi-step procedures and coupling reactions, enabling the synthesis of complex oligosaccharides [90].

A recently synthesized, multitargeting Hep-based mimetic, necuparanib, was shown to attenuate pancreatic cancer tumor cell growth and invasion in a three-dimensional (3D) culture model. In contrast, in vivo, it facilitated survival and attenuated the metastatic ability of pancreatic cancer cells. Furthermore, the proteomic analysis demonstrated that necuparinib, among others, targeted ECM-originating mediators, well established to affect cancer cell growth and metastasis. Specifically, necuparanib attenuated the expression of metalloproteinase 1 (MMP1) and facilitated the expression of tissue inhibitor of metalloproteinase 3 (TIMP3) in the 3D pancreatic cancer model [91]. Moreover, the levels of TIMP3 in the plasma of patients with metastatic pancreatic cancer who were participating in a phase I/II study treatment with necuparanib plus standard therapy were found to be substantially enhanced [91].

A crucial therapeutic target is cancer-associated angiogenesis. Both fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF) can form ternary complexes with HS and their respective cell-membrane receptors, initiating signaling cascades that facilitate angiogenesis [92]. These growth factors are characterized as important cancer therapy targets with Hep mimetics’ possible implementation [93][94]. The d-mannose-based sulfated oligosaccharide mixture, PI-88 (Muparfostat) is one such inhibitor. It is developed from the oligosaccharide phosphate fraction obtained from the extracellular phosphomannan, initially derived from the yeast Pichia (Hansenula) holstii (NRRL Y-2448) and subsequently extensively sulfated [95][96].

Modified LMWH functionalized by polystyrene (NAC-HCPS) exhibited increased affinity to HS binding growth factors and attenuated anticoagulant properties, decreased endothelial cell growth, and formation of endothelial tubes [97]. Moreover, SST0001 Hep derivatives, characterized by 100% N-acetylated, 25% glycol split Hep SST0001 (100NA-ROH, roneparstat), efficiently reduced FGF2-mediated proliferation of endothelial and lymphoid cells and displayed a limited capacity to release FGF from the ECM. This effect is associated with the N-acetylation of GlcN.SST0001 and was also reported to counteract human sarcoma cell invasion induced by exogenous FGF2 [98]. Interestingly, Hep is actively uptaken by melanoma cells and affects their migration and adhesion [99].

The disadvantages of using Hep derivatives, discussed above, are mostly correlated to the intrinsic Hep anticoagulant properties to initiate severe hemorrhagic effects.

3.2. Enzymatic Modulation of HS–Protein Interactions

Heparanase, the only mammalian enzyme responsible for HS/Hep cleavage, is a strict endo-β-glucuronidase, favoring the fission of a GlcA linked to 6O-sulfated GlcN, which can either be N-sulfated or N-acetylated [56]. However, advances have implicated the potential controlling role of the surrounding saccharide sequences and their sulfation pattern in regulating the extent of substrate degradation [56]. This plasticity of substrate specificity enhances the execution of various heparanases’ roles [100]. The cleavage of HS chains bound into PGs releases latent growth factors, including FGF2, hepatocyte growth factor (HGF), keratinocyte growth factor (FGF4), and TGF-β, which are sequestered to the matrix and cell surface, but also inherently modulates the protein-GAG interactions and downstream signaling [101]. Indeed, trimming of HS can enhance the binding of growth factors to their respective receptors, as in the case of FGF-2 where the creation of tertiary FGF2-FGFR-HS complex is increased by moderate heparanase activity [102]. Moreover, heparanase was found to reside and accumulate in lysosomes suggesting that it also exhibits intracellular functions [103].

Heparanase strongly affects protein–HS interactions, whereas tumor-associated activated fibroblasts, endothelial cells, and immune cells exhibit increased heparanase activity [104]. The overexpression of heparanase results in vivo in increased tumor metastasis, whereas downregulating heparanase markedly decreases cancer cells’ ability to metastasize [105].

Heparanase expression was shown to be upregulated in all cancer types, including sarcomas, carcinomas, and hematological neoplasms [106]. Notably, heparanase activity has been correlated to various human cancers’ metastatic potential. Thus, the examination of the Cancer Genome Atlas (TCGA) data on heparanase expression in breast cancer clinical samples showed its upregulation in the majority of specimens. Furthermore, increased heparanase expression was correlated with poor patient survival [107]. Similar results have been obtained for other cancer types, including multiple myeloma [108] and bladder cancer [109]. Moreover, heparanase has been shown to affect cancer angiogenesis [110], invasion, and autophagy [111] and partly through syndecan-1-dependent mechanisms to modulate inflammation-associated tumorigenesis [112].

Heparanase can affect the response to chemotherapy. Thus, anti-myeloma chemotherapeutic agents, including bortezomib (proteasome inhibitor) or melphalan (alkylating agent), were shown to increase the expression and secretion of heparanase in an in vitro myeloma model. The subsequent uptake of soluble heparanase by tumor cells initiated ERK and Akt signaling pathways, stimulated the expression of vascular endothelial growth factor (VEGF), HGF, and MMP-9, and was correlated with an aggressive tumor phenotype [113].

An essential mechanism of heparanase action is promoting exosome secretion, which affects both tumor and host cells’ biological behavior and finally drives tumor progression [114]. In a myeloma model, it was shown that chemotherapeutic drugs increase exosome secretion. Notably, chemoexosomes have an increased heparanase load, enhancing cell HS’s cleaving activity and initiating ERK signaling and syndecan-1 shedding. These authors suggest that anti-myeloma therapy stimulates the secretion of high heparanase content exosomes, facilitates ECM remodeling, changes tumor and stroma cell behavior, and contributes to chemoresistance [115].

Several therapeutic approaches have been tested to develop efficient inhibitors of heparanase activity. Non-anticoagulant heparin derivatives such as SST0001 or roneparstat significantly downregulated heparanase-dependent cleavage of syndecan-1 HS chains, attenuated HGF, VEGF, and MMP-9 expression resulting in decreased tumor growth and angiogenesis in vivo [116][117]. Preclinical evidence resulted in the first human study (NCT01764880) assessing the safety and tolerability of roneparstat in patients with relapsed or refractory multiple myeloma (MM). Patients treated with Roneparstat exhibited acceptable tolerance at clinically significant doses [118].

PI-88 is an inhibitor of heparanase, in addition to its antagonist of angiogenic growth factors function [119]. Even though it exerted adjuvant properties in hepatocellular carcinoma and melanoma patients [120][121], PI88 has been correlated with bleeding events, and thus, did not progress to clinical practice [122].

A series of PI-88 analogs have been synthesized, exhibiting superior performance. The improved analogs comprise single, characterized oligosaccharides with discrete functionalizations and exhibit more efficient antagonism of angiogenic growth factors and respective receptors binding with HS. These properties are translated into potent inhibition of growth factor-dependent endothelial cell growth and strong downregulation of the endothelial tube formation [119]. PG545 is the outstanding member of the PI88 analogs series exhibiting significant anti-angiogenic, anti-proliferation, and antimetastatic effects through potent heparanase inhibitory and angiogenic growth factor antagonist effects [123]. Moreover, PG545 was shown to exert anti-tumor effects discrete from heparanase inhibition as it induces lymphoma cell apoptosis in a non-heparanase-dependent manner [124]. PG545 (pixatimod) is currently being tested in clinical trials [123]. However, despite promising breakthroughs, the development of heparanase inhibitors with a beneficial clinical performance and acceptable adverse effects is still elusive. Therapeutics targeting HS are summarized in Table 1.

Table 1. Therapeutics targeting HS.

Therapy
Target		 Drug Cancer Type Stage Reference
Antagonists of angiogenic growth factors necuparanib Pancreatic cancer 3D model, animal tumor model, Phase I/II clinical trial in combination with standard therapy [91]
PI-88 (muparfosfat) General tumor angiogenesis In vitro, animal models [95][96]
NAC-HCPS Lung tumor Animal model [97]
Hep SST0001 (roneparstat) Sarcoma Animal models [98]
Heparanase
Inhibitors		 SST0001 (roneparstat) Multiple myeloma Animal model, Clinical trial [117][118]
PI-88
(muparfosfat)		 Hepatocellular
Carcinoma. melanoma		 Clinical trial [120][121]
PI-88 analogs (PC545-pixatimod) Human lymphoma Animal model,
Clinical trial		 [122][123]

However, some studies targeting heparanase demonstrated contradictory results. In some model systems, inactive heparanase facilitated adhesion and migration of endothelial cells and induced factors that promote angiogenesis, such as vascular endothelial growth factor [125]. The enzyme has a C-terminus domain involved in the molecule’s signaling capacity. The human heparanase variant (T5) lacking enzymatic activity has protumorigenic properties, indicating the enzyme’s complex role in cancer pathogenesis [125].

This entry is adapted from the peer-reviewed paper 10.3390/biom11030395

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