Xanthophyll β-Cryptoxanthin Inhibits High-Refined Carbohydrate Diet-Promoted Hepatocellular Carcinoma Progression in Mice.

β-Cryptoxanthin (BCX), a provitamin A carotenoid, can be cleaved by both beta-carotene 15,15'-oxygenase (BCO1) and beta-carotene 9',10'-oxygenase (BCO2) generating biological active vitamin A and apocarotenoids. The aim of this study was to determine whether BCX feeding could inhibit diethylnitrosamine (DEN)-initiated, high-refined carbohydrate diet (HRCD)-promoted hepatocellular carcinoma (HCC) development, dependent or independent of BCO1/BCO2 activity.

Two-week-old male wild-type (WT) and BCO1^-/- /BCO2^-/- double knock-out (DKO) mice were given a single intraperitoneal injection of DEN (25 mg/kg body weight) to initiate hepatic carcinogenesis. At six weeks of age, all animals were fed HRCD (66.5% of energy from carbohydrate) with or without BCX for 24 weeks. BCX feeding increased hepatic vitamin A levels in WT mice, but not in DKO mice that showed a significant accumulation of hepatic BCX. Compared to their respective HRCD littermates, both WT and DKO fed BCX had significantly lower HCC multiplicity (58-60%), average tumor size (21-24%), and total tumor volume (51-58%), and the steatosis scores. The chemopreventive effects of BCX were associated with increased p53 protein acetylation and gluconeogenesis markers (phosphoenolpyruvate carboxykinase, glucose 6-phosphatase) and decreased protein levels of a glycolysis marker (lactate dehydrogenase) and of the hypoxia-inducible factor-1α and its downstream targets, matrix metalloproteinase 2/9 in tumors.

This study suggests that BCX feeding may alleviate HRCD-promoted HCC progression by modulating the acetylation of p53, hypoxic tumor microenvironment and glucose metabolism, independent of BCO1 and BCO2. This article is protected by copyright. All rights reserved.