Suramin inhibits hepatic tissue damage in hepatocellular carcinoma through deactivation of heparanase enzyme

Tayel, Ahmed A.; Galil, Khaled H. Abd El; Ebrahim, Mohamed A.; Ibrahim, Ahmed S.; El-Gayar, Amal M.; Al‐Gayyar, Mohammed M.H.

doi:10.1016/j.ejphar.2014.02.001

Cited by 31 publications

(18 citation statements)

References 54 publications

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“…The drug discovery of small molecule inhibitors of heparanase has been delayed due to lack of structural information. These inhibitors include iminosugars and other putative transition-state analogues, substrate analogues, inhibitors discovered via screening of compound libraries, and natural products and their derivatives (Li et al, 2013; Rivara et al, 2016; Simizu et al, 2004; Tayel et al, 2014). Now that the crystal structure of human heparanase has been resolved (Wu et al, 2015), studies are ongoing to develop structure-based heparanase-inhibiting small molecules.…”

Section: Heparanase Inhibitors In Cancer Therapymentioning

confidence: 99%

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Vlodavsky¹,

Singh²,

Boyango³

et al. 2016

Drug Resistance Updates

195

229

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Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physiopathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy.

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Section: Heparanase Inhibitors In Cancer Therapymentioning

confidence: 99%

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Vlodavsky¹,

Singh²,

Boyango³

et al. 2016

Drug Resistance Updates

195

229

View full text Add to dashboard Cite

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“…It has been found to inhibit heparanase activity in melanoma, cervical, hepatocellular and ovarian cancer cell lines. 146–148 It has not transitioned into clinical trials because its side-effect profile is too toxic. Multiple others have been studied and none have reached clinical trials.…”

Section: Heparanase Inhibitors As Novel Cancer Therapeuticsmentioning

confidence: 99%

Mechanisms of heparanase inhibitors in cancer therapy

Heyman

Yang

2016

Experimental Hematology

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Heparanase is an endo-β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains contributing to break down of the extracellular matrix. Increased expression of heparanase has been found in numerous malignancies, and is associated with a poor prognosis. It has generated significant interest as a potential anti-neoplastic target because of the multiple roles it plays in tumor growth and metastasis. The pro-tumorigenic effects of heparanase are enhanced by the release of HS side chains, with subsequent increase in bioactive fragments and increased cytokine levels; both promoting tumor invasion, angiogenesis and metastasis. Preclinical experiments have shown heparanase inhibitors to substantially reduce tumor growth and metastasis leading to clinical trials with heparan sulfate mimetics. In this review we will examine heparanase’s role in tumor biology, its interaction with heparan surface proteoglycans, specifically syndecan-1; as well as the mechanism of action for heparanase inhibitors developed as anti-neoplastic therapeutics.

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“…The animals were randomly divided into seven groups of 10 rats [12] each as described below: in group 1 (normal control) rats were p.o. injected 0.5% CMC solution (vehicle used for preparing the extract and isoepoxypteryxin) for 18 w, twice/week; group 2 (extract; EXT) rats were p.o.…”

Section: Experimental Animalsmentioning

confidence: 99%

“…single dose of 350 mg/kg [20] to HCC with a chronic i.p. dose of 200 mg/kg [21,22] . It is well established that from the 16 th w of the TAA treatment, a whitish, visible HCC tumours are well observed [23] .…”

Section: Table 1: Effect Of Different Group Treatment On Histopatholomentioning

confidence: 99%

Hepatoprotective Activities of the Methanol Extract of Angelica shikokiana and Isoepoxypteryxin against Hepatocellular Carcinoma

Mira¹,

Elsherbiny²,

Alkhiary³

et al. 2017

pharmaceutical-sciences

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JapanMira, et al.: Hepatoprotective Activity of Angelica shikokiana Angelica shikokiana (Apiaceae) is a Japanese traditional herb and widely marketed as a dietary food supplement as a health tea preparation consumed as a daily beverage for its health benefits. Our previous research showed that the methanol extract of the aerial parts of A. shikokiana and its major coumarin, isoepoxypteryxin had a significant cytotoxicity against HepG2 cell line. In this study, we investigated the hepatoprotective activity more deeply by the in vitro inhibition of HepG2 cells invasion assay and in vivo using thioacetamide-induced hepatocellular carcinoma model in rats. The ex vivo levels of nitric oxide production, inducible nitric oxide synthase, vascular endothelial cell growth factor-C and caspase-3 were also estimated to investigate the possible mechanisms of hepatoprotection. The methanol extract of A. shikokiana and isoepoxypteryxin concentration-dependently depressed the invasion of HepG2 cells induced by 12-O-tetradecanoylphorbol 13-acetate. In vivo, they significantly reduced the levels of alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase, total bilirubin and nitric oxide production when compared with hepatocellular carcinoma group. Besides, the thioacetamide-injected groups treated with methanol extract of A. shikokiana and isoepoxypteryxin exhibited a significant increase in the level of caspase-3 protein and a significant decrease of inducible nitric oxide synthase and vascular endothelial cell growth factor C levels when compared with hepatocellular carcinoma group. To the best of our knowledge, this is the first report of the hepatoprotective effect of A. shikokiana and isoepoxypteryxin against hepatocellular carcinoma.

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Suramin inhibits hepatic tissue damage in hepatocellular carcinoma through deactivation of heparanase enzyme

Cited by 31 publications

References 54 publications

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Mechanisms of heparanase inhibitors in cancer therapy

Hepatoprotective Activities of the Methanol Extract of Angelica shikokiana and Isoepoxypteryxin against Hepatocellular Carcinoma

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