Natural-Product-Inspired Compounds as Countermeasures against the Liver Carcinogen Aflatoxin B₁

Area of Science:

• Toxicology
• Natural Product Chemistry
• Drug Discovery

Background:

• Aflatoxin B1 (AfB1) is a potent liver carcinogen posing a global health risk to humans and livestock.
• Current therapeutic strategies to mitigate AfB1 toxicity have shown limited clinical success.
• Identifying novel molecular scaffolds for AfB1 detoxification is crucial.

Purpose of the Study:

• To develop and utilize a high-throughput cell-based assay for screening natural products against AfB1 toxicity.
• To identify protective molecular scaffolds that can mitigate AfB1-induced liver cell damage.
• To explore the potential of spheroids as a more sensitive model for AfB1 toxicity assessment.

Main Methods:

• Development of a cell-based high-throughput high-content imaging assay using HepG2 liver cells.
• Testing of natural products, including pure compounds, fractions, and extracts, for protective effects against AfB1.
• Comparison of monolayer and spheroid cell culture models to assess AfB1 sensitivity and response.
• Synthesis and evaluation of structurally related molecules based on promising natural product leads.

Main Results:

• A high-throughput screening assay successfully identified compounds with protective activity against AfB1.
• HepG2 spheroids demonstrated increased sensitivity to AfB1, better mimicking in vivo hepatocyte response.
• Alternariol-9-methyl ether was identified as a highly bioactive compound.
• Structurally related polyarene molecules, particularly those with 3-methoxyphenol moieties, showed significant potential.

Conclusions:

• Natural products can serve as a valuable source for identifying AfB1 protective agents.
• The spheroid-based assay is a promising platform for future AfB1 toxicity research and drug discovery.
• Oxidatively functionalized polyarene molecules represent a promising class of compounds for developing novel therapeutics against aflatoxin B1 toxicity.