Umbelliferone β-d-galactopyranoside inhibits chemically induced renal carcinogenesis via alteration of oxidative stress, hyperproliferation and inflammation: possible role of NF-κB

Abstract

Umbelliferone (7-hydroxycoumarin) possesses strong anti-inflammatory properties and free radical scavenging activity. The intent of the current study was to examine the renal protective efficacy of Umbelliferone β-D-galactopyranoside (UFG) against oxidative stress, inflammation and renal injury in Wistar rats, initiated by diethylinitrosamine (DEN) and promoted by ferric nitrilotriacetate (Fe-NTA). The capacity of UFG to scavenge the reactive nitrogen species (RNS) and reactive oxygen species (ROS) was evaluated and was also scrutinized for its effectiveness in scavenging the hydroxyl (OH), superoxide (O₂), nitric acid (NO) and hydrogen peroxide (H₂O₂) radicals. Renal carcinoma was induced by a single intraperitoneal injection of DEN (200 mg kg⁻¹ bodyweight) and promoted by twice weekly treatment of Fe-NTA (9 mg kg⁻¹) for 22 weeks. To estimate the molecular mechanism involved in the antitumor potential of UFG, its effect on renal tumor inflammation was evaluated; the proinflammatory cytokines included interleukin-1β (IL-1β), interlukin-6 (IL-6) and tumor necrosis factor (TNF-α); the inflammatory mediator included prostaglandin E₂ (PGE₂), ornithine decarboxylase (ODC) and nuclear factor kappa B cell (NFκB). Serum abnormalities, including creatinine, lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and [³H] thymidine incorporation were also induced. Furthermore, renal lipid peroxidation (LPO), endogenous antioxidant enzymes, phase II metabolizing enzymes and concomitant reduction in glutathione (GSH) were augmented. UFG showed the 95% and 99% antioxidant activity in the 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) models. UFG significantly inhibited the RNS and ROS radical and indicated the antioxidant activity (in vitro). The results showed momentous renal markers and oxidative stress protection impaired by UFG. UFG also restored the altered inflammatory and proinflammatory cytokines, which further strengthens the renal protection of UFG in DEN + Fe-NTA induced renal carcinogenesis. These results indicate that UFG is an efficient chemoprotective agent, having the ability to thwart DEN induced and Fe-NTA promoted renal carcinoma in experimental rats.