# Investigating the In Vitro Mitochondria-Mediated Anticancer Activity of the Plant Metabolite Ursolic Acid

## TL;DR

This study shows that ursolic acid, a plant compound, kills breast cancer cells by targeting mitochondria and works better when combined with glycolysis inhibitors.

## Contribution

The study reveals a direct mitochondrial inhibitory effect of ursolic acid and proposes a novel dual treatment strategy for breast cancer.

## Key findings

- Ursolic acid induces cytotoxicity and antiproliferative effects in breast cancer cells.
- Ursolic acid depolarizes mitochondrial membrane potential and inhibits mitochondrial enzyme activity.
- Combining ursolic acid with glycolytic inhibitors enhances cytotoxicity in breast cancer cells.

## Abstract

This study investigated the cellular and mitochondrial toxicities of the pentacyclic triterpenoid and plant-specialized metabolite ursolic acid (UA) in human breast adenocarcinoma cell lines. Cell viability and clonogenic assays showed that UA induced potent cytotoxic and antiproliferative effects in MDA-MB-231 and MCF7 cells. Confocal images of living cells showed that UA caused a depolarization of the mitochondrial membrane potential and spectrophotometric measurement of electron transport chain enzyme activity in isolated organelles showed that UA induced a dose-dependent decrease in mitochondrial succinate-cytochrome reductase activity. These results demonstrate a direct, site-specific inhibitory effect of UA on mitochondrial bioenergetic function. Furthermore, the efficacy of a drug combination aimed concurrently at both major pathways of ATP production in breast cancer cells was investigated. The data show that when MDA-MB-231 and MCF7 cells were treated with UA in combination with either 2-deoxy-D-glucose or 3-bromopyruvate, two inhibitors of glycolysis, the resulting cytotoxicity was greater than that induced by any of the compounds used independently. The results of this study are important in that they demonstrate direct mitochondrial targets of UA and suggest the possibility of using this natural, plant-derived metabolite in combination with glycolytic inhibitors as a novel and effective dual treatment strategy for breast cancer cell killing.