# Toward Mitochondrial Targeting of Resistant Triple-Negative Breast Cancer Using Triphenylphosphonium-Conjugated Antimicrobial Peptides

## TL;DR

This study explores using peptides linked to a mitochondrial-targeting compound to fight resistant breast cancer by disrupting cancer cell energy production.

## Contribution

The novel approach involves conjugating antimicrobial peptides with triphenylphosphonium to target resistant cancer cells' mitochondria.

## Key findings

- TPP-conjugated peptides reduced metastatic potential and CSC-like mammosphere formation in resistant breast cancer cells.
- These compounds induce oxidative stress and mitophagy while suppressing mitochondrial translation.
- The strategy shows promise for targeting OXPHOS-dependent resistance in aggressive tumors.

## Abstract

Metastatic evolution
of malignant tumors following standard anticancer
therapies and the emergence of resistant cancer cell populations remain
major challenges in oncology. One promising strategy is to develop
compounds that selectively target mechanisms of therapeutic resistance.
Unlike therapy-sensitive malignant cells, which rely primarily on
glycolysis for energy, many chemoresistant cells and cancer stem cells
(CSCs) preferentially utilize mitochondrial oxidative phosphorylation
(OXPHOS). In this study, we employed a triple-negative breast cancer
model to demonstrate that short antimicrobial peptides can significantly
suppress the metastatic potential of resistant cancer cells and reduce
the formation of CSC-like mammospheres by disrupting mitochondrial
respiration. This effect was further enhanced by conjugating the peptides
to the mitochondrial-targeting cation triphenylphosphonium (TPP).
Mechanistic studies revealed that these compounds induce oxidative
stress and mitophagy and suppress mitochondrial translation. Collectively,
these findings suggest that TPP-conjugated peptides represent a promising
therapeutic strategy for targeting OXPHOS-dependent resistance in
aggressive solid tumors.