# Punicalin Modulates Angiogenesis and Tumor Microenvironment-Related Processes in Triple-Negative Breast Cancer and Endothelial Cells

## TL;DR

Punicalin, a natural compound, affects cancer and endothelial cells by modulating oxidative stress and autophagy, potentially inhibiting tumor growth and angiogenesis.

## Contribution

This study reveals punicalin's selective effects on triple-negative breast cancer and endothelial cells, particularly its impact on oxidative stress and angiogenesis.

## Key findings

- Punicalin reduces oxidative stress in MDA-MB-231 cells and modulates ROS in HMEC-1 cells.
- Punicalin significantly inhibits angiogenic capacity in endothelial cells.
- Punicalin decreases tumor cell migration and HMEC-1 migration without affecting HUVEC migration.

## Abstract

The tumor microenvironment plays a critical role in cancer progression, with oxidative stress, autophagy, angiogenesis, and cell migration acting as tightly interconnected processes. Natural bioactive compounds have emerged as promising modulators of these pathways; however, their cell type-specific effects within the TME remain poorly understood. In this study, we investigate the effects of punicalin on triple-negative breast cancer and endothelial cells, with a focus on redox homeostasis and autophagy as upstream regulatory mechanisms. Punicalin reduced oxidative stress in MDA-MB-231 cells under basal conditions and strongly attenuated hydrogen peroxide-induced stress, whereas HMEC-1 cells exhibited concentration- and condition-dependent reactive oxygen species (ROS) modulation. Autophagy assays revealed no significant modulation in tumor cells, while a consistent and pronounced decrease in autophagic activity was observed in endothelial cells under both basal and nutrient-deprivation conditions. Functionally, punicalin decreased tumor cell migration and impaired HMEC-1 migration, while HUVEC migration remained largely unaffected. Tube formation assays demonstrated significant inhibition of angiogenic capacity. Taken together, these findings demonstrate that punicalin selectively modulates oxidative stress and autophagy, leading to functional alterations in migration and angiogenesis. By highlighting its selective impact on microvascular endothelial cells while sparing normal endothelium, this study provides a strong rationale for further preclinical evaluation of punicalin.