Title:Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance
Volume: 24
Issue: 26
关键词:
硫酸肝素蛋白聚糖，乙酰肝素酶，硫酸乙酰肝素模拟物，乙酰肝素酶抑制剂，硫酸酯酶抑制剂，抗癌药物抗药性，抗癌化疗。
摘要: 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.
