Suramin inhibits hepatic tissue damage in hepatocellular carcinoma through deactivation of heparanase enzyme.
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 of suramin in in-vivo model of HCC. Therefore, HCC was induced in SD rats by thioacetamide (200 mg/kg) in presence/absence of suramin (20 mg/kg). Liver impairment was assessed by measuring serum α-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. Suramin increased the animal survival and decreased serum α-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. Abbreviations AFP, α-fetoprotein; ALT, alanine aminotransferase; cDNA, complementary DNA; Ct, threshold Cycle; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; H/E, hematoxylin and eosin; HS, heparan sulfate; HSPGs, heparan sulfate proteoglycans; IHC, immunohistochemistry; I.P., intra peritoneal; MDA, malondialdhyde; Rpm, revolution per min; RT-PCR, real-time polymerase chain reaction; S.E.M, standard error of the mean; SOD, superoxide Dismutase; TNF, tumor necrosis factor Chemical compounds studied in this article Glucosamine (PubChem CID: 441477); Glucuronic acid (PubChem CID: 94715); Malondialdehyde (PubChem CID: 10964); Suramin (PubChem CID: 8514); Thioacetamide (PubChem CID: 2723949) Keywords Extrinsic cell death; Fibroblast Growth Factor (FGF)-2; Glucosamine; Glucuronic acid; Heparan sulfate proteoglycans (HSPGs); Intrinsic cell death
Tayel A, Abd El Galil KH, Ebrahim MA, Ibrahim AS, El-Gayar AM
Eur J Pharmacol.,Volume 728, Page 151-160