Review article
Antitumor activity and structure-activity relationship of heparanase inhibitors: Recent advances

https://doi.org/10.1016/j.ejmech.2020.112221Get rights and content

Highlights

  • Heparanase (HPSE) inhibitors effectively block tumor growth, invasion and metastasis and regain drug susceptibility.

  • HPSE inhibitors are elaborated according to interaction with the binding sites of HPSE and participation of growth factors.

  • Antitumor activity and SAR of HPSE inhibitors are also discussed and emphasized.

  • Rational discovery of HPSE inhibitors with favorable druggability profiles is proposed.

Abstract

Heparanase (HPSE)-directed tumor progression plays a crucial role in mediating tumor-host crosstalk and priming the tumor microenvironment, leading to tumor growth, metastasis and chemo-resistance. HPSE-mediated breakdown of structural heparan sulfate (HS) networks in the extracellular matrix (ECM) and basement membranes (BM) directly facilitates tumor growth and metastasis. Lysosome HPSE also induces multi-drug resistance via enhanced autophagy. Therefore, HPSE inhibitors development has become an attractive topic to block tumor growth and metastasis or eliminate drug resistance. In this review, we summarize HPSE inhibitors applied experimentally and clinically according to interaction with the binding sites of HPSE and participation of growth factors. The antitumor activity and structure-activity relationship (SAR) are also emphasized.

Graphical abstract

Heparanase (HPSE) inhibitors are classified into three types to be discussed according to interaction with the binding sites of HPSE and participation of growth factors. The antitumor activity and structure-activity relationship are also emphasized.

Image 1
  1. Download : Download high-res image (128KB)
  2. Download : Download full-size image

Introduction

Heparanase (HPSE), an endo-β-D glucuronidase, is exclusively expressed in mammalian cells. It has two isozymes HPSE1 and HPSE2, encoded by two genes respectively, but HPSE2 lacks enzymatic activity and acts predominantly as a negative regulator of HPSE1 [1]. HPSE, usually referred to HPSE1, comprises two functional domains, an (α/β)8 barrel catalytic domain and a β-sandwich C-terminal domain. In the catalytic domain, the residues Glu343 and Glu225 are responsible for the catalytic nucleophile and catalytic acid/base of HPSE enzymatic cleaving activity, respectively [2]. The C-terminal domain has been demonstrated to regulate protein secretion and non-enzymatic activity of HPSE [3]. Significant aggressiveness and chemo-resistance of multiple tumor cells are largely dependent on the enzymatic or non-enzymatic activities of HPSE. On the one hand, HPSE specifically cleaves the β (1,4)-glycosidic bond between residues glucuronic acid and glucosamine (Fig. 1) of heparan sulfate (HS) attached to proteoglycans via enzymatic activity [4], latent pools of growth factors sequestered by HS are subsequently released, posing remodeling of ECM and BM [5]. On the other hand, HPSE regulates gene expression, activates the innate immune system, promotes the formation and release of exosomes and autophagosomes, as well as stimulates signal transduction pathways by virtue of non-enzymatic activity [4]. These HPSE-mediated bio-functions play a strong positive role in regulating tumor-host crosstalk and priming the tumor microenvironment to support tumor growth, metastasis and chemo-resistance.

The inactive pro-HPSE (65 kDa) is a HPSE precursor, which is synthesized in the endoplasmic reticulum (ER), an activity that stimulates signaling cascades to enhance phosphorylation of specific proteins including Akt, Src, and ERK. Then the pro-HPSE is processed in the Golgi and resultant HPSE is stored in the lysosomes and endosomes. Activated HPSE could be released to the extracellular space, the surface of exosomes, and autophagosomes, or even shuttled into the nucleus. HPSE located in late endosomes and lysosomes performs an essential housekeeping role in catabolic processing of internalized heparan sulfate proteoglycans (HPSGs). Extracellular HPSE effects degradation and turnover of cell surface HSPGs via an enzymatic approach. Also, HPSE enters the intracellular to stimulate release of growth factors, which are secreted into the extracellular space, further posing pathological conditions (Fig. 2). Moreover, HPSE in the lysosomes and autophagosomes can positively stimulate the autophagic process through a non-enzymatic mechanism due to downregulation of mTOR1 activity [6,7]. Collectively, the enzymatic and non-enzymatic activities make HPSE a multifunctional molecule that deteriorates aggressiveness and chemo-resistance in multiple tumor cells [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]].

As discussed above, HPSE is a promising and potential antitumor target. HPSE inhibition has attracted intense interest as an anticancer strategy. The putative binding site of HPSE orientates as a canyon-like cleft, which is made up of several polar and nonpolar amino acid residues [27]. The resolved co-crystal structure of complex HPSE protein and its substrate provides a powerful design basis for HPSE inhibitors [28]. A trisaccharide is a minimal substrate for HPSE because less than three sugar residues do not well accommodate into the binding cleft of HPSE, and an appropriated sulfation is required for the interaction with HPSE and HS. HPSE inhibitors reported are demonstrated to inhibit HPSE activity through competitively binding to the HS-binding sites of HPSE, or simultaneously binding to the HS-binding sites of HPSE and growth factors, or binding to the non HS-binding sites of HPSE [29]. To date, a series of HPSE inhibitors such as PG545, SST0001, M402 and PI-88 are evaluated in clinical trials for cancer therapy. PG545 exhibited a long plasma half-life and showed an excellent activity against HPSE, and Phase I clinical trials were completed in 2015 [30]. SST0001 exhibited a low-anticoagulant activity, selectively inhibited HPSE and related growth factors [31], and Phase I trials were finished in 2016 [30]. M402 showed a low-anticoagulant activity and a good potential for HPSE inhibition, but it was halted after Phase I trials [30,32]. PI-88 has entered into phase III clinical trials for treating liver cancer [33]. Apparently, HPSE inhibitors are potent and promising anti-cancer agents.

The roles of HPSE in cancer progression are very crucial and widely accepted. Understanding the subtle binding mode of HPSE and its substrates is an attractive solution to cancer therapy. HPSE inhibitors development has demonstrated a promising strategy for suppressing tumor growth, metastasis and chemo-resistance. Although several reviews focusing on the status of natural, chemically modified, and synthetic HPSE inhibitors able to treat various types of malignancies have been reported [30,[34], [35], [36]], the structure-activity relationships are not clearly pointed out. Herein, the recent advance of HPSE inhibitors as promising anti-tumor drugs is stated from a new perspective of interaction with the binding sites of HPSE and participation of growth factors, and the inhibitory activity and structure-activity relationship are highlighted, in hope to provide a novel guiding direction for developing more effective HPSE inhibitors.

Section snippets

Endogenous HP/HS-based HPSE inhibitors

Heparin (HP) is a highly sulfated HS that is an endogenous substrate of HPSE. HS mimics represent good candidates as anticancer agents targeting HPSE inhibition. Heparin mimics act as substrate analogues to competitively inhibit HP binding to HPSE, such as modified heparins and PI-88. These compounds demonstrated the improved activity against HPSE, the excellent bioavailability and the reduced side effects [37]. When co-administered with other anti-cancer agents, tumor resistance was eliminated.

Conclusion and future outlook

Most HPSE inhibitors competitively target to the HS/HP-binding sites of HPSE and thus prevent HS access to the catalytic domains. Structurally, they are divided into two types including carbohydrate-based inhibitors and non-carbohydrate-based ones [29]. For the carbohydrate-based inhibitors, most mainly inhibit HPSE activities as competitive inhibitors of HS, e.g. HS analogues, PI-88, SST0001, M402, PS3, JG3, COs, azasugar-derived analogues, HS-derived glycomimetic clusters, etc. However, PG545

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The work is supported in part by financial support from National Natural Science Foundation of China (No.21772028), General scientific research project of Guangzhou (201804010325) and “Climbing” progress of Guangdong province (pdjh2019a0111, pdjh2020b0139).

References (155)

  • A. Naggi et al.

    Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting

    J. Biol. Chem.

    (2005)
  • B. Heyman et al.

    Mechanisms of heparanase inhibitors in cancer therapy

    Exp. Hematol.

    (2016)
  • G. Cassinelli et al.

    Supersulfated low-molecular weight heparin synergizes with IGF1R/IR inhibitor to suppress synovial sarcoma growth and metastases

    Canc. Lett.

    (2018)
  • R.I. Bouças et al.

    Glycosaminoglycan backbone is not required for the modulation of hemostasis: effect of different heparin derivatives and non-glycosaminoglycan analogs

    Matrix Biol.

    (2012)
  • V. Ferro et al.

    Determination of the composition of the oligosaccharide phosphate fraction of Pichia (Hansenula) holstii NRRL Y-2448 phosphomannan by capillary electrophoresis and HPLC

    Carbohydr. Res.

    (2002)
  • G. Yu et al.

    Preparation and anticoagulant activity of the phosphosulfomannan PI-88

    Eur. J. Med. Chem.

    (2002)
  • M.A. Rosenthal et al.

    Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia

    Ann. Oncol.

    (2002)
  • K. Nyberg et al.

    The low molecular weight heparan sulfate-mimetic, PI-88, inhibits cell-to-cell spread of herpes simplex virus

    Antivir. Res.

    (2004)
  • H.P. Wessel et al.

    The smooth muscle cell antiproliferative activity of heparan sulfate model oligosaccharides

    Bioorg. Med. Chem. Lett

    (1996)
  • A.-K. Schoenfeld et al.

    Testing of potential glycan-based heparanase inhibitors in a fluorescence activity assay using either bacterial heparinase II or human heparanase

    J. Pharmaceut. Biomed. Anal.

    (2014)
  • Z. Csíki et al.

    The 4-nitrobenzenesulfonyl group as a convenient N-protecting group for iminosugars synthesis of oligosaccharide inhibitors of heparanase

    Tetrahedron Lett.

    (2010)
  • K. Allen et al.

    Syntheses of novel azasugar-containing mimics of heparan sulfate fragments as potential heparanase inhibitors

    Carbohydr. Res.

    (2010)
  • Z. Csíki et al.

    Synthesis of glycosaminoglycan oligosaccharides. Part 4: synthesis of aza-l-iduronic acid-containing analogs of heparan sulfate oligosaccharides as heparanase inhibitors

    Tetrahedron

    (2010)
  • E.T. Sletten et al.

    Glycosidase inhibition by multivalent presentation of heparan sulfate saccharides on bottlebrush polymers

    Biomacromolecules

    (2017)
  • R. Rondanin et al.

    Arylamidonaphtalene sulfonate compounds as a novel class of heparanase inhibitors

    Bioorg. Med. Chem. Lett

    (2017)
  • L. Borsig et al.

    Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase

    Neoplasia

    (2011)
  • P.K. Qasba

    Involvement of sugars in protein protein interactions

    Carbohydr. Polym.

    (2000)
  • M. Guerrini et al.

    Synthesis and characterisation of hexa- and tetrasaccharide mimics from acetobromomaltotriose and acetobromomaltose, and ofC-disaccharide mimics from acetobromoglucose, obtained by electrochemical reduction on silver

    Tetrahedron Asymmetry

    (2005)
  • M.J. van den Hoven et al.

    Heparanase in glomerular diseases

    Kidney Int.

    (2007)
  • S.M. Courtney et al.

    2,3-Dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid derivatives: a novel class of small molecule heparanase inhibitors

    Bioorg. Med. Chem. Lett

    (2004)
  • Y.J. Xu et al.

    N-(4-{[4-(1H-Benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamide derivatives as small molecule heparanase inhibitors

    Bioorg. Med. Chem. Lett

    (2006)
  • W. Pan et al.

    1-[4-(1H-Benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea derivatives as small molecule heparanase inhibitors

    Bioorg. Med. Chem. Lett

    (2006)
  • R. Gozalbes et al.

    Hit identification of novel heparanase inhibitors by structure- and ligand-based approaches

    Bioorg. Med. Chem.

    (2013)
  • S. Courtney et al.

    Furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acid derivatives: novel classes of heparanase inhibitor

    Bioorg. Med. Chem. Lett

    (2005)
  • Basappa et al.

    A small oxazine compound as an anti-tumor agent: a novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-α

    Canc. Lett.

    (2010)
  • L. Zhang et al.

    Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer

    Neoplasia

    (2015)
  • L. Wu et al.

    Structural characterization of human heparanase reveals insights into substrate recognition

    Nat. Struct. Mol. Biol.

    (2015)
  • M.D. Hulett et al.

    Identification of active-site residues of the pro-metastatic endoglycosidase heparanase

    Biochemistry

    (2000)
  • V. Masola et al.

    Role of heparanase in tumor progression: molecular aspects and therapeutic options

    Semin. Canc. Biol.

    (2019)
  • A. Shteingauz et al.

    Heparanase enhances tumor growth and chemoresistance by promoting autophagy

    Canc. Res.

    (2015)
  • T.J. Rabelink et al.

    Heparanase: roles in cell survival, extracellular matrix remodelling and the development of kidney disease

    Nat. Rev. Nephrol.

    (2017)
  • Q. Lv et al.

    Interleukin 17A and heparanase promote angiogenesis and cell proliferation and invasion in cervical cancer

    Int. J. Oncol.

    (2018)
  • C. Zeng et al.

    Heparanase overexpression participates in tumor growth of cervical cancer in vitro and in vivo

    Med. Oncol.

    (2013)
  • J. Li et al.

    Heparanase promotes radiation resistance of cervical cancer by upregulating hypoxia inducible factor 1

    Am. J. Cancer Res

    (2017)
  • C.J. Simeonovic et al.

    Heparanase and autoimmune diabetes

    Front. Immunol.

    (2013)
  • H. Zheng et al.

    Heparanase is involved in proliferation and invasion of ovarian cancer cells

    Canc. Biomarkers : A Dis. Markers

    (2015)
  • S. Kundu et al.

    Heparanase promotes glioma progression and is inversely correlated with patient survival

    Mol. Canc. Res.

    (2016)
  • O. Kazarin et al.

    Expression of heparanase in soft tissue sarcomas of adults

    J. Exp. Clin. Canc. Res.

    (2014)
  • M. Hao et al.

    NEK2 induces osteoclast differentiation and bone destruction via heparanase in multiple myeloma

    Leukemia

    (2017)
  • U. Barash et al.

    Heparanase enhances myeloma progression via CXCL10 downregulation

    Leukemia

    (2014)
  • View full text