Inhibition of bladder tumor growth by chitooligosaccharides in an experimental carcinogenesis model

Abstract

Urinary bladder cancer is one of the most common cancers worldwide, with the highest incidence in industrialized countries. Patients with cancer commonly use unconventional and complementary therapy including nutraceuticals. In this study we evaluated the efficacy of chitooligosaccharides (in orange juice) in rat bladder cancer chemoprevention and as therapeutic agent, on a rat model of urinary bladder carcinogenesis induced with N-butyl-N-(4-hydroxybutyl) nitrosamine. Results indicate that chitooligosaccharides may have a preventive effect on bladder cancer development and a curative effect upon established bladder tumors, dependent on the concentration ingested 500 mg/kg b.w., every three days, showed capacity to inhibit and prevent the proliferation of bladder cancer; however, this was associated with secondary effects such as hypercholesterolemia and hypertriglyceridemia. The use of lower doses (50 and 250 mg/kg b.w.) showed only therapeutic effects. It is further suggested that this antitumor effect might be due to its expected anti-inflammatory action, as well as by mechanisms not directly dependent of COX-2 inhibition, such as cellular proliferation control and improvement in antioxidant profile.

Figure 1

Structure of chitin and chitosan. Chitin is composed mainly by (b) units while chitosan is composed predominantly by (a) units (>50%). Ac—acetyl group.

Figure 2

Macroscopic evaluation of the bladders, at the end of the 20 week-protocol: A—group control; B—group N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN); C—group T-BBN + chitosan oligosaccharides (COS)(50); D—group P-COS(50) + BBN; E—group T-BBN + COS(250); F—group P-COS(250) + BBN; G—group T-BBN + COS(500); H—group P-COS(500) + BBN.

Figure 3

Microscopic histomorphology (H & E). The typical bladder from control group (A) and control groups with COS (B) treated-rats had no signs of pre-neoplasic lesions or gross tumor formation. In the carcinogen groups, the bladder from several animals presented hyperplasia (C and D) (groups T-BBN + COS(50), P-COS(250) + BBN and BBN) and high-grade dysplasia (E and F) (groups T-BBN + COS(50), P-COS(50) + BBN, T-BBN + COS(250), P-COS(250) + BBN, T-BBN + COS(500) and BBN), including those without tumor formation, as well as malignant lesions, such as papillary tumors (G and H) (groups 2, 3, 5, 6, 8, 9 and 10) or infiltrative (I) (group 10).

Figure 4

Redox status markers: lipidic peroxidation (MDA content) in liver (A), kidney (B) and serum (C); serum TAS (D).