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.
Quercetin, the plant-derived phenolic compounds, plays a pivotal role in controlling hemostasis, by having potent antioxidant and free-radical scavenging properties. This flavonoid in combination with chemotherapeutic drugs improves the efficacy of these agents in induction of apoptosis in cancer cells. This study investigated the role of nano-quercetin (phytosome) in doxorubicin-induced apoptosis. Nanoparticles were characterized for particle size, zeta potential, scanning electron microscopy (SEM) and differential scanning calorimetric assessments. Anti-proliferative effect of formulations was evaluated by MTT assay. mRNA expression levels of target genes were measured by real time RT-PCR. The mean size of nanoparticles was 85 ± 2 nm with nearly narrow size distribution which was confirmed by SEM analysis. Our results showed that co-treatment of MCF-7 breast cancer cells with nano-quercetin and doxorubicin increased the percentage of apoptosis from 40.11 ± 7.72-58 ± 7.13 (p < 0.05). Furthermore, mRNA expression levels for downstream genes including NQO1 and MRP1 showed a marked decrease (p < 0.05). Taken together, our results suggest that phytosome technology can elevate the efficacy of chemotherapeutics by increasing the permeability of tumor cells to chemical agents. Our findings introduce a novel phytosome-dependent strategy to improve delivery of doxorubicin to the breast cancerous tissues.
Abstract.The balance between the production and elimination of reactive oxygen species (ROS) is essential in determining whether cells survive or undergo apoptosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) may act as a sensor for electrophilic stress, thus regulating the intracellular antioxidant response. The present study investigated the role of vitamin C (VC) and quercetin (Q) in the induction of Nrf2-mediated oxidative stress in cancer cells. An MTT assay was conducted to examine the anti-proliferative effects of VC and Q. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to determine the messenger RNA (mRNA) and protein expression of Nrf2, respectively. The activity of nicotinamide adenine dinucleotide phosphate dehydrogenase quinone 1, heme oxygenase 1, glutathione peroxidase, glutathione reductase and reduced glutathione were measured by spectrophotometric analysis. Intracellular generation of ROS was determined using 2'-7'-dichlorodihydrofluorescein diacetate fluorescent probes. The results demonstrated that the cytotoxicity (50% inhibitory concentration) of VC and Q were 271.6-480.1 and 155.1-232.9 µM, respectively. Additionally, there was a significant decrease in the expression of Nrf2 mRNA and protein levels following the treatment of breast cancer cells with VC and Q (P=0.024). Following treatment with VC and Q, the nuclear/cytosolic Nrf2 ratio was reduced by 1.7-fold in MDA-MB 231 cells, 2-fold in MDA-MB 468 cells, 1.4-fold in MCF-7 cells and 1.2 fold in A549 cells. Sequential treatment with VC and Q decreased endogenous production of ROS in a dose-dependent manner (P=0.027). The results of the current study suggest that VC and Q treatment may be developed as an adjuvant for patients with cancer and overexpression of Nrf2.
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