Heparanase: A Challenging Cancer Drug Target
| Autor: | Neha S. Gandhi, Deirdre R. Coombe |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Cell tumor progression Review heparin lcsh:RC254-282 drug discovery heparanase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo medicine cancer Heparanase heparanase-2 Drug discovery drug Cancer Heparan sulfate lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 111207 Molecular Targets 030104 developmental biology medicine.anatomical_structure Oncology chemistry Tumor progression 030220 oncology & carcinogenesis Cancer research 060112 Structural Biology (incl. Macromolecular Modelling) heparan sulfate Function (biology) |
| Zdroj: | Frontiers in Oncology Frontiers in Oncology, Vol 9 (2019) |
| ISSN: | 2234-943X |
| DOI: | 10.3389/fonc.2019.01316 |
| Popis: | Heparanase has been viewed as a promising anti-cancer drug target for almost two decades, but no anti-heparanase therapy has yet reached the clinic. This endoglycosidase is highly expressed in a variety of malignancies, and its high expression is associated with greater tumor size, more metastases, and a poor prognosis. It was first described as an enzyme cleaving heparan sulfate chains of proteoglycans located in extracellular matrices and on cell surfaces, but this is not its only function. It is a multi-functional protein with activities that are enzymatic and non-enzymatic and which take place both outside of the cell and intracellularly. Knowledge of the crystal structure of heparanase has assisted the interpretation of earlier structure-function studies as well as in the design of potential anti-heparanase agents. This review re-examines the various functions of heparanase in light of the structural data. The functions of the heparanase variant, T5, and structure and functions of heparanase-2 are also examined as these heparanase related, but non-enzymatic, proteins are likely to influence the in vivo efficacy of anti-heparanase drugs. The anti-heparanase drugs currently under development predominately focus on inhibiting the enzymatic activity of heparanase, which, in the absence of inhibitors with high clinical efficacy, prompts a discussion of whether this is the best approach. The diversity of outcomes attributed to heparanase and the difficulties of unequivocally determining which of these are due to its enzymatic activity is also discussed and leads us to the conclusion that heparanase is a valid, but challenging drug target for cancer. |
| Databáze: | OpenAIRE |
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