# Targeting Redox Homeostasis and Cell Survival Signaling with a Flavonoid-Rich Extract of Bergamot Juice in In Vitro and In Vivo Colorectal Cancer Models

## TL;DR

This study shows that a flavonoid-rich extract from bergamot juice can reduce colorectal cancer growth in lab and animal models by affecting cell survival and DNA damage.

## Contribution

The novel contribution is demonstrating the anti-cancer effects of bergamot juice extract in both in vitro and in vivo CRC models with detailed mechanistic insights.

## Key findings

- Bergamot juice extract inhibited CRC cell growth and induced apoptosis in HCT-116 cells.
- The extract caused DNA damage and reduced the number of aberrant crypt foci in a mouse model of CRC.
- Bergamot juice extract lowered tumor and polyp occurrence in mice with AOM-induced CRC.

## Abstract

Background/Objectives: Colorectal cancer (CRC) is the second most common cause of cancer death worldwide. Evidence suggests that a polyphenol-rich diet may lower the risk of CRC. The aim of this study was to demonstrate the potential antitumor effects of a flavonoid-rich extract of bergamot juice (BJe) in both in vitro and in vivo CRC models, assessing the underlying mechanisms. Methods: CRC cells, among which HCT-116, have been employed to assess the fine mechanism of action of BJe, whereas a mouse model of azoxymethane (AOM)-induced CRC was exploited to appreciate the anti-cancer effects of BJe. Results: BJe inhibited the growth of several CRC cells, especially HCT-116. In this cell line, BJe induced apoptosis and blocked the cell cycle in the G1 phase, as well as modulated the gene expression of apoptosis- and cell cycle-related factors. Moreover, BJe prompted reactive oxygen species production and impaired mitochondrial membrane potential. In the nucleus of these cancerous cells, BJe induced DNA damage as confirmed by the raised levels of 8-oxo-2′-deoxyguanosine and phosphorylation of histone H2A.X. In mice with AOM-induced CRC, BJe was able to lower the number of aberrant crypt foci. Moreover, BJe reduced the percentage of mice bearing both polyps and tumors, as well as their number. Conclusions: Our study supports the role of BJe against CRC, providing knowledge on the underlying mechanism of action.