Potential Chemopreventive Role of Boldine Against Hepatocellular Carcinoma via Modulation of Cell Cycle Proteins in Rat Model

Abstract

Background: To evaluate the chemopreventive potential of boldine against diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in wistar albino rats. Objective: Boldine is an alkaloid isolated from Peumus boldus. The primary active constituents of boldine exhibited several potential medicinal properties. The present study was evaluated to explore the chemopreventive agent of boldine on anti-proliferative efficacy against diethylnitrosamine (DEN) induced hepatocellular carcinoma (HCC) in wistar albino rats. Methods: The effect of boldine on cellular proliferative markers, i.e., PCNA and Ki67 on hepatocellular carcinoma rats was determined by immuno expression study. Liver marker enzymes, tumor biomarker, oxidative stress markers, anti-oxidant status and xenobiotic phase I and II enzymes in HCC rats were analyzed. Moreover, cell cycle proteins, i.e., p21Cip1/Kip1, p27 Cip1/Kip1, Cyclin D1, CDK 4, Cyclin E1, and CDK 2 were investigated using immuno expression analysis. Results: Treatment of boldine protected the liver against reactive oxygen species such as hydrogen peroxide, superoxide, protein carbonyl and lipid peroxide during hepatocarcinogenesis by boosted antioxidants-superoxide dismutase (SOD), catalase (CAT). Boldine caused substantial enhanced detoxification process by moderating phase I and II xenobiotic metabolizing enzymes. In addition, the study was found that boldine significantly inhibited the cellular proliferative markers like PCNA and Ki67 and regulated the specific cell cycle associated proteins by up-regulated expression of p21Cip1/Kip1 and p27 Cip1/Kip1 and down-regulated expression of Cyclin D1, CDK 4, Cyclin E1, and CDK 2. Conclusion: Our data manifests the anti-proliferative effect of boldine, which negatively modulates cellular proliferation and regulates cell cycle by protecting the cell from reactive oxygen species (ROS), suggesting that boldine establish it as a chemopreventive agent in diethylnitrosamine-induced hepatocarcinogenesis in rats.

Boldine protects against carbon tetrachloride‐induced chronic liver injury by regulating NF‐κB signaling pathway

“…[8] From the liver perspective, boldine has been shown to protect the liver against oxidative stress, cholestasis and drug-induced liver injury in experimental studies. [13,18,19] In an in vivo study, boldine administration reduced liver microsomal lipid peroxidation, suppressing oxidative stress in rat models. [20] Methylprednisolone and acetaminophen-induced hepatotoxicities were significantly alleviated after boldine administration due to its antioxidant, anti-inflammatory and antiapoptotic effects.…”