Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models

Cassinelli, Giuliana; Lanzi, Cinzia; Tortoreto, Monica; Cominetti, Denis; Petrangolini, Giovanna; Favini, Enrica; Zaffaroni, Nadia; Pisano, Claudio; Penco, Sergio; Vlodavsky, Israël; Zunino, Franco

doi:10.1016/j.bcp.2013.02.023

Cited by 74 publications

(84 citation statements)

References 38 publications

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“…This structure allowed these compounds compete with HS binding to heparanase to inhibit the activity of heparanase. Reported heparanase inhibitors such as PI-88, PG545, and SST0001 are all close structural homologue of endogenous glycosaminoglycans (29)(30)(31)(32)(33). The anticoagulant agent heparin also belongs to the mimics of HS and has been used as a heparanase inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…Heparanase caused ECM collapse also led to release of heparin-binding cytokines like HGF, VEGF, and bFGF which promote tumor angiogenesis (26,27). Such an irreplaceable role in cancer metastasis and angiogenesis makes heparanase an appealing target for cancer therapy (28)(29)(30)(31)(32)(33). However, there is no heparanase inhibitor available in clinical to date.…”

Section: Introductionmentioning

confidence: 99%

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Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Dai

Yan

et al. 2017

Clinical Cancer Research

102

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Dai

Yan

et al. 2017

Clinical Cancer Research

102

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“…Pazopanib, sorafenib, sunitinib, regorafenib and axitinib were all dissolved in 0.5% carboxymethylcellulose and delivered by oral gavage 5 days/week for 4 weeks (qd Â 5d/w Â 4w) Â 2 after a 3-week rest at their reported optimal dose of 100/60/40/ 30 and 2 Â 25 mg/kg, respectively. Bevacizumab was delivered intraperitoneally twice a week for 4 weeks (q3-4d/w Â 4w) Â 2 after a 3-week rest at its reported optimal dose of 4 mg/kg [12][13][14][15][16]. Control mice were treated with vehicle.…”

Section: Xenograft Treatmentmentioning

confidence: 99%

Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour

Stacchiotti

Tortoreto

Baldi

et al. 2014

European Journal of Cancer

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Background: To explore the activity of pazopanib in solitary fibrous tumour (SFT). Patients and methods: In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm 3 . Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure.

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“…In addition to growth inhibition of the tumour, in this experiment SST0001 reduced angiogenesis. In another paper researchers reported that SST0001 inhibited growth of sarcoma tumours, which was probably associated with the anti-angiogenic activity of this chemically modified heparin [41]. An orally active LMWH conjugate, LHTD4, exhibited anti-cancer activity, which was probably associated with the anti-angiogenic properties of LHTD4 [42], and a similar anti-metastatic activity was also revealed by some selectin-specific heparin derivatives [26,43].…”

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confidence: 76%

Administration of low molecular weight heparins for prolonging the survival of patients with cancer

Majewski¹,

Simka²

2015

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Thromboembolism represents one of the most common causes of mortality and morbidity in cancer patients, and thromboembolic events occur more often in patients with biologically more aggressive malignant disease. Therefore, low molecular weight heparins (LMWHs) are routinely administered to cancer patients. Importantly, in addition to the prophylactic activity against thromboembolism, LMWHs seem to decrease mortality in these patients. Improved clinical prognosis is independent of the antithrombotic efficacy, since vitamin K antagonists do not improve patient survival, and non-anticoagulant heparins exhibit a similar anti-cancer effect. This protective effect is primarily related to the prevention of spreading of the cancer through metastases. The mechanisms responsible for heparin-dependent inhibition of metastases comprise: inhibition of integrins, restraint of P-and L-selectin-mediated interactions of the platelets with circulating neoplastic cells, silencing of the chemokine CXCL12/CXCR4 axis, inhibition of heparanase activity, inhibition of neoangiogenesis within the tumour, and reduced local generation of thrombin. A combined effect of the above-described mechanisms is also possible. Although at the moment cancer patients are not recommended routine administration of LMWHs for survival improvement, such a recommendation might be expected in the future. It is possible that for this purpose, instead of currently available agents, some novel heparins or similarly structured chemical compounds will be used. In the FAMOUS trial, carried out on a subgroup of patients with good clinical prognosis, administration of LMWH significantly improved their survival [17]. In the MALT study, administration of LMWH resulted in improved survival in cancer patients with advanced malignancy with a life expectancy of more than six months [29]. Similarly, cancer patients with good clinical prognosis benefited from LMWH administration in the CLOT study [19]. Also, a post-hoc analysis of the results of the PROTECHT study revealed improved survival, but only in patients responding to chemotherapy [30], while this beneficial effect was not seen in those not responding to the treatment [31]. On the other hand, such an anti-cancer protective effect was not found in other clinical trials assessing the survival benefit of LMWH administration. However, these trials examined patients with an advanced malignancy and poor clinical prognosis [32,33].Analysis of the above-mentioned trials suggests that in selected groups of cancer patients LMWHs improve survival irrespective of the antithrombotic efficacy of the drug, since vitamin K antagonists did not improve clinical prognosis [19]. Besides, this anti-cancer effect did not result from an inhibition of primary tumours, but rather from anti-metastatic activity [34,35]. Consequently, two published meta-analyses [36,37] suggest that LMWHs can improve the survival of cancer patients, primarily those with non-metastatic disease. It is also possible that at least some patients with advance...

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Antitumor efficacy of the heparanase inhibitor SST0001 alone and in combination with antiangiogenic agents in the treatment of human pediatric sarcoma models

Cited by 74 publications

References 38 publications

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Aspirin Inhibits Cancer Metastasis and Angiogenesis via Targeting Heparanase

Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour

Administration of low molecular weight heparins for prolonging the survival of patients with cancer

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