Novel Biochemical Pathways for 5-Fluorouracil in Managing Experimental Hepatocellular Carcinoma in Rats

Abstract

Five fluorouracil (5-FU) is extensively used in the treatment of hepatocellular carcinoma (HCC). It is well documented that 5-FU and its metabolites inhibit DNA synthesis through inhibition of thymidylate synthetase. Little is known about additional pathways for 5-FU in managing HCC. The present experiment was mainly designed to study possible biochemical pathways that can be added to 5-FU's mechanisms of action. Four groups of rats constituted a control group (given saline only), a trichloroacetic acid group (TCA, 0.5 g/kg/day for 5 days, orally), a 5-FU-positive group (75 mg/kg body weight, intraperitoneally, once weekly for 3 weeks) and a TCA-treated with 5-FU group (24 h from last TCA dose). We executed both biochemical-serum alpha-fetoprotein (AFP), liver tissue contents of total glycosaminoglycan (TGAGs), collagen (represented as hydroxyproline), total sialic acid (TSA), free glucosamine (FGA) and proteolytic enzyme activity (as pepsin and free cathepsin-D-and histological examinations of the liver tissue. The results revealed histological changes such as central vein congestion and irregularly shaped, substantially enlarged, vesiculated and binucleated hepatocytes. The nuclei were mostly polymorphic and hyperchromatic, and several vacuolation was noticed in the cytoplasm encircling the nucleus with masses of acidophilic material. 5-FU greatly corrected these changes, except that some necrotic and cytotoxic effects of 5-FU were still shown. AFP was significantly elevated in TCA-intoxicated, but reversed in 5-FU-treated, groups. Increased proteolytic activity by TCA was reversed by 5-FU, which also restored TGAG contents to normal; but both TCA and 5-FU depleted collagen content. TCA significantly elevated FGA but depressed TSA; this action was reversed by 5-FU treatment. In conclusion, it is possible that proteolytic activity, expressed as upregulated pepsin and free cathepsin-D activities, is increased in HCC. This is accompanied by extracellular matrix macromolecular disturbance, manifested as decreased TGAGs, collagen and TSA, with marked increase in FGA liver tissue content. The elevated FGA with depressed TSA content of liver tissue may be attributed to a cancer-hampered N-acetylation of FGA into SA. 5-FU administration markedly depressed hepatic tissue proteolysis, possibly reactivated N-acetylation of FGA into SA and elevated TGAGs without stopping tissue fibrosis as collagen was not affected. This study explores additional pathways for the mechanism of action of 5-FU, through conservation of extracellular matrix composition in situ, inhibiting invasion and metastasis in addition to its DNA-disturbing pathway.

Hepatocyte Lysosomal Membrane Stabilization by Olive Leaves against Chemically Induced Hepatocellular Neoplasia in Rats

“…This early upregulatory impact of TCA on proteolytic enzymes may contribute to the mechanism of cancer induction and invasion by this substance, an action that was noticed in some previous publications [39, 40]. Administration of AOLE alone maintained some proteolytic enzyme activities within normal values, except an elevation of papain activity to a significant level.…”

Antimetastatic therapy targeting aberrant sialylation profiles in cancer cells

“…41 Similar to our standpoint, AbdeHamid NM et al reported that some anticancer drugs that did not show typical antimetastatic effects, such as 5-Fu, could not inhibit sia levels in tumor cells. 44 These work show the inhibitions of sias in tumors can be a good model to study antimetastatic drugs than antiproliferative drugs and be significance for studying their underlying mechanisms. This is a relatively new therapeutic target for us to study.…”

Antimetastatic therapy at aberrant sialylation in cancer cells, a potential hotspot

“…It involved from bioassays to anti-proliferative evaluation to anti-metastatic responses in murine tumor models (Lewis lung carcinoma and melanoma B16). The therapeutic studies of sias-related Antimetastatic drugs began at approximately 30 years ago [12,25,[36][37][38][39][40][41][42][43][44][45][46]. Since this type of anticancer drugs (especially targeting sias in tumors) has been seldom entering into clinical investigations, most experimental therapeutic studies have been collected here.…”

“…However, some licensed anticancer drugs such as 5-Fu that do not show typical Antimetastatic effects are also unable to inhibit sialic acid levels in tumor cells [44].…”