Luteolin-loaded Phytosomes Sensitize Human Breast Carcinoma MDA-MB 231 Cells to Doxorubicin by Suppressing Nrf2 Mediated Signalling

Abstract

Nuclear factor erythroid 2-related factor 2 (Nrf2) has been recognized as a transcription factor that controls mechanisms of cellular defense response by regulation of three classes of genes, including endogenous antioxidants, phase II detoxifying enzymes and transporters. Previous studies have revealed roles of Nrf2 in resistance to chemotherapeutic agents and high level expression of Nrf2 has been found in many types of cancer. At physiological concentrations, luteolin as a flavonoid compound can inhibit Nrf2 and sensitize cancer cells to chemotherapeutic agents. We reported luteolin loaded in phytosomes as an advanced nanoparticle carrier sensitized MDA-MB 231 cells to doxorubicin. In this study, we prepared nano phytosomes of luteolin to enhance the bioavailability of luteolin and improve passive targeting in breast cancer cells. Our results showed that cotreatment of cells with nano particles containing luteolin and doxorubicin resulted in the highest percentage cell death in MDA-MB 231cells (p<0.05). Furthermore, luteolin-loaded nanoparticles reduced Nrf2 gene expression at the mRNA level in cells to a greater extent than luteolin alone (p<0.05). Similarly, expression of downstream genes for Nrf2 including Ho1 and MDR1 were reduced significantly (p<0.05). Inhibition of Nrf-2 expression caused a marked increase in cancer cell death (p<0.05). Taken together, these results suggest that phytosome technology can improve the efficacy of chemotherapy by overcoming resistance and enhancing permeability of cancer cells to chemical agents and may thus be considered as a potential delivery system to improve therapeutic protocols for cancer patients.

Doxorubicin Changes Bax /Bcl-xL Ratio, Caspase-8 and 9 in Breast Cancer Cells

“…29 Different strategies have been developed for analysis and study of this cancer. [30][31][32][33] MCF-7 cell line is an excellent in vitro model for studying the mechanisms of chemoresistance as it is susceptible to apoptosis and applied for various investigations on apoptosis or survival of cancer cells. [34][35][36] Although the extensive clinical application of doxorubicin for cancer patients has been studied, its anti-proliferative and death-inducing signalling cascades are yet unclear.…”

Skin Redox Balance Maintenance: The Need for an Nrf2-Activator Delivery System

“…This study provided additional proof for the strategy of prevention and controlling oxidative stress-related pathophysiological conditions in aging [239]. An additional example providing justification for the development of an Nrf2-activator delivery system and expanding its potential application was executed with luteolin loaded phytosomes resulting in the sensitization of MDA-MB-231 cells to doxorubicin [240].…”

Formulation and Evaluation of Phytosome-Loaded Maltodextrin-Gum Arabic Microsphere System for Delivery of Camellia sinensis Extract

“…Phytosomes are also carriers that can increase the therapeutic efficacy of the green tea leaf extract. 8 Phytosomes have better abilities than herbal extracts in terms of their absorption through the intestinal lipid membrane. 9 In addition to its absorption and bioavailability problems, EGCG also has limitations on its stability, i.e.…”