Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Abstract

Purpose: Recent epidemiological and clinical studies have suggested the benefit of aspirin for patients with cancer, which inspired increasing efforts to demonstrate the anticancer ability of aspirin and reveal the molecular mechanisms behind. Nevertheless, the anticancer activity and related mechanisms of aspirin remain largely unknown. This study aimed to confirm this observation, and more importantly, to investigate the potential target contributed to the anticancer of aspirin.Experimental Design: A homogeneous time-resolved fluorescence (HTRF) assay was used to examine the impact of aspirin on heparanase. Streptavidin pull-down, surface plasmon resonance (SPR) assay, and molecular docking were performed to identify heparanase as an aspirin-binding protein. Transwell, rat aortic rings, and chicken chorioallantoic membrane model were used to evaluate the antimetastasis and anti-angiogenesis effects of aspirin, and these phenotypes were tested in a B16F10 metastatic model, MDA-MB-231 metastatic model, and MDA-MB-435 xenograft model.Results: This study identified heparanase, an oncogenic extracellular matrix enzyme involved in cancer metastasis and angiogenesis, as a potential target of aspirin. We had discovered that aspirin directly binds to Glu225 region of heparanase and inhibits the enzymatic activity. Aspirin impeded tumor metastasis, angiogenesis, and growth in heparanase-dependent manner.Conclusions: In summary, this study has illustrated heparanase as a target of aspirin for the first time. It provides insights for a better understanding of the mechanisms of aspirin in anticancer effects, and offers a direction for the development of smallmolecule inhibitors of heparanase.

Anticancer IrIII–Aspirin Conjugates for Enhanced Metabolic Immuno‐Modulation and Mitochondrial Lifetime Imaging

“…MTT assays showed the compounds to have low cytotoxicity at this concentration (Figure S33). Similar phenomena were also observed for SA and As , consistent with literature reports that anti‐angiogenesis is involved in the anticancer properties of As …”

“…Similarp henomena were also observed for SA and As,c onsistent with literature reports that anti-angiogenesis is involved in the anticancer properties of As. [59]…”

Aspirin acts in esophageal cancer: a brief review

“…For the antiangiogenic effect, aspirin down-regulates heparanaserelated VEGF levels which decreases tumor angiogenetic activity. They further verified the binding sites for aspirin in heparanase as Lys159 and Glu225, which may propose new inhibitors of heparanase by binding to these two sites (60).…”

“…A recent study of Dai and her colleges suggested heparanase participating in the antitumor activity of aspirin through affecting the metastasis and angiogenesis of tumor cells (60).…”

Complex roles of the old drug aspirin in cancer chemoprevention and therapy

“…Moreover, aspirin inhibits hydroxyacid‐oxoacidtranshydrogenase‐mediated production of (R)‐2‐hydroxyglutarate, a metabolite that promotes some kinds of tumors . A recent study demonstrates that aspirin inhibits cancer metastasis and angiogenesis via targeting heparanase . In addition, aspirin reportedly inhibits tumor growth and stemness in colorectal cancer by downregulating Nanog .…”