Title:Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance
Volume: 24
Issue: 26
Author(s): Cinzia Lanzi*, Nadia Zaffaroni and Giuliana Cassinelli*
Affiliation:
- Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Experimental Oncology and Molecular Medicine, Molecular Pharmacology Unit, via Amadeo 42, 20133 Milan,Italy
- Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Experimental Oncology and Molecular Medicine, Molecular Pharmacology Unit, via Amadeo 42, 20133 Milan,Italy
Keywords:
Heparan sulfate proteoglycan, heparanase, heparan sulfate mimic, heparanase inhibitor, sulfatase inhibitor,
anticancer drug resistance, anticancer chemotherapy.
Abstract: Targeting heparan sulfate proteoglycans (HSPGs) and enzymes involved in heparan
sulfate (HS) chain editing is emerging as a new anticancer strategy. The involvement of
HSPGs in tumor cell signaling, inflammation, angiogenesis and metastasis indicates that
agents able to inhibit aberrant HSPG functions can potentially act as multitarget drugs affecting
both tumor cell growth and the supportive boost provided by the microenvironment. Moreover,
accumulating evidence supports that an altered expression or function of HSPGs, or of
the complex enzyme system regulating their activities, can also depress the tumor response to
anticancer treatments in several tumor types. Thereby, targeting HSPGs or HSPG modifying
enzymes appears an appealing approach to enhance chemotherapy efficacy. A great deal of
effort from academia and industry has led to the development of agents mimicking HS, and/or
inhibiting HSPG modifying enzymes. Inhibitors of Sulf-2, an endosulfatase that edits the HS
sulfation pattern, and inhibitors of heparanase, the endoglycosidase that produces functional
HS fragments, appear particularly promising. In fact, a Sulf-2 inhibitor (OKN-007), and two
heparanase inhibitors/HS mimics (roneparstat, PG545) are currently under early clinical investigation.
In this review, we summarized preclinical studies in experimental tumor models of
the main chemical classes of Sulf-2 and heparanase inhibitors. We described examples of different
mechanisms through which heparanase and HSPGs, often in cooperation, may impact
tumor sensitivity to various antitumor agents. Finally, we reported a few preclinical studies
showing increased antitumor efficacy obtained with the use of candidate clinical HS mimics in
combination regimens.
