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

Tayel A, Abd El Galil KH, Ebrahim MA, Ibrahim AS, El-Gayar AM, Al-Gayyar MM.

Eur J Pharmacol. 2014 Apr 5;728:151-60.

Deptment of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt and

Deptment of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt and

Oncology Center, University of Mansoura, Mansoura 35516, Egypt and

Deptment of Clinical Biochemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt. Electronic address: [email protected]

 

Abstract

 

Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy. Heparanase, enzyme attacks heparan sulfate proteoglycans (HSPGs), is preferentially expressed in human tumors and its overexpression in low-metastatic tumor confers a highly invasive phenotype in experimental animals. Meanwhile, high doses of suramin dramatically increase tissue glycosaminoglycans due, in part, to inhibition of heparanase enzymes. Therefore, the following study was conducted to evaluate the chemopreventive and hepatoprotective effects ofsuramin in in-vivo model of HCC. Therefore, HCC was induced in SD rats by thioacetamide (200mg/kg) in presence/absence of suramin (20mg/kg). Liver impairment was assessed by measuring serum {Alpha}-fetoprotein and investigating liver sections stained with Hematoxylin/Eosin. Hepatic HSPGs and heparanse were measured by ELISA. Glucosamine and glucuronic acid were measured by chemical methods. Gene expression of fibroblast growth factor (FGF)-2 and caspase-3 was measured. Apoptotic pathway was evaluated by measuring the activity of caspase-3/8/9. Suraminincreased the animal survival and decreased serum {Alpha}-fetoprotein. In addition, suramin ameliorated fibrosis and massive hepatic tissue breakdown.Suramin restored hepatic HSPGs and reduced the activity of hepatic heparanase leading to decreased hepatic levels of glucosamine and glucuronic acid. Moreover, suramin reduced the gene expression of FGF-2 and caspase-3. Finally, suramin blocked the elevated activity of caspase-3/8/9. In conclusion, surmain showed antitumor activity as well as hepatoprotective effects. Besides its antioxidant activity, other mechanisms are involved including restoration of HSPGs and inhibition of heparanase and FGF-2. Suramin inhibits intrinsic and extrinsic apoptotic pathway. Targeting HSPGs expression is potential therapeutic target for HCC.

Copyright © 2014 Elsevier B.V. All rights reserved.

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