Targeting Heparanase in Cancer: Inhibition by Synthetic, Chemically Modified, and Natural Compounds

Chakrabhavi Dhananjaya Mohan; Swetha Hari; Habbanakuppe D Preetham; Shobith Rangappa; Uri Barash; Neta Ilan; S Chandra Nayak; Vijai K Gupta; Basappa; Israel Vlodavsky; Kanchugarakoppal S Rangappa

doi:10.1016/j.isci.2019.04.034

Targeting Heparanase in Cancer: Inhibition by Synthetic, Chemically Modified, and Natural Compounds

iScience. 2019 May 31:15:360-390. doi: 10.1016/j.isci.2019.04.034. Epub 2019 May 3.

Authors

Affiliations

¹ Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India.
² Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
³ Adichunchanagiri Institute for Molecular Medicine, AIMS Campus, B. G. Nagar, Nagamangala Taluk, Mandya District 571448, India.
⁴ Technion Integrated Cancer Center (TICC), The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
⁵ Department of Studies in Biotechnology, University of Mysore, Manasagangotri, Mysore 570006, India.
⁶ Department of Chemistry and Biotechnology, ERA Chair of Green Chemistry, School of Science, Tallinn University of Technology, Tallinn, Estonia.
⁷ Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.
⁸ Technion Integrated Cancer Center (TICC), The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel. Electronic address: vlodavsk@mail.huji.ac.il.
⁹ Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India. Electronic address: rangappaks@yahoo.com.

Abstract

Heparanase is an endoglycosidase involved in remodeling the extracellular matrix and thereby in regulating multiple cellular processes and biological activities. It cleaves heparan sulfate (HS) side chains of HS proteoglycans into smaller fragments and hence regulates tissue morphogenesis, differentiation, and homeostasis. Heparanase is overexpressed in various carcinomas, sarcomas, and hematological malignancies, and its upregulation correlates with increased tumor size, tumor angiogenesis, enhanced metastasis, and poor prognosis. In contrast, knockdown or inhibition of heparanase markedly attenuates tumor progression, further underscoring the potential of anti-heparanase therapy. Heparanase inhibitors were employed to interfere with tumor progression in preclinical studies, and selected heparin mimetics are being examined in clinical trials. However, despite tremendous efforts, the discovery of heparanase inhibitors with high clinical benefit and minimal adverse effects remains a therapeutic challenge. This review discusses the key roles of heparanase in cancer progression focusing on the status of natural, chemically modified, and synthetic heparanase inhibitors in various types of malignancies.

Keywords: Biological Sciences; Cell Biology; Glycobiology; Molecular Biology.

Publication types

Review

Grants and funding

R01 CA211752/CA/NCI NIH HHS/United States