The Anti-Cancer Effects of Mitochondrial-Targeted Triphenylphosphonium–Resveratrol Conjugate on Breast Cancer Cells

Abstract

Breast cancer is the most commonly diagnosed cancer in women. Resveratrol, a naturally occurring phytochemical, shows great promise in developing novel anti-cancer therapies. This study hypothesized that the mitochondria-targeted delivery of resveratrol would increase its potency and induce mitochondria-mediated apoptosis. The targeted delivery of resveratrol was achieved by conjugating resveratrol to triphenylphosphonium (TPP). The anti-cancer effects of TPP-resveratrol were studied in the murine breast cancer 4T1 and the human breast cancer MDA-MB-231 cell lines. Flow cytometry was used to study apoptosis induction, cell cycle arrest, and mitochondrial membrane potential loss. The morphological changes in the mitochondria in MDA-MB-231 cells after TPP-resveratrol treatments were examined using transmission electron microscopy. Moreover, the changes in MDA-MB-231 cell metabolism after resveratrol and TPP-resveratrol treatments were studied using metabolomic analysis. We demonstrate that TPP-resveratrol significantly improved cytotoxicity in 4T1 cells and MDA-MB-231 cells by inducing apoptosis and mitochondrial membrane potential loss. Swollen and vacuolated mitochondria were observed after the TPP-resveratrol treatment. Meanwhile, TPP-resveratrol treatment down-regulated amino acid and energy metabolism and caused the dysfunction of purine and pyrimidine metabolism. Our results provide evidence supporting the targeted delivery of resveratrol to mitochondria and suggest that TPP-resveratrol may be an effective agent for breast cancer treatment.

Mechanism of action of resveratrol affecting the biological function of breast cancer through the glycolytic pathway

“…In recent years, resveratrol has gained signi cant attention from scholars both domestically and internationally due to its effective anti-tumor activity. Resveratrol has been found to inhibit breast cancer both in vivo and in vitro, and its mechanism of action is closely related to various molecular targets including cell proliferation, epithelial-mesenchymal transition, chemosensitization, invasion and metastasis, apoptosis, and epigenetics [24,25]. Numerous preclinical experiments have demonstrated that resveratrol inhibits the expression of histone transferase EZH2 by regulating the dephosphorylation of protein kinase ERK1/2, resulting in the inhibition of growth and proliferation of breast cancer cells [26].…”

Recent Advances in Nanotechnology-Based Targeted Delivery Systems of Active Constituents in Natural Medicines for Cancer Treatment

“…Triphenylphosphine (TPP), a non-localized cationic group composed of three benzene rings, is commonly used to mediate chemotherapeutic drugs or nano-preparations to overcome the obstruction of biomembranes and, subsequently, target mitochondria [20,184,185].…”