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Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a transcriptional factor which acts as a regulator for cellular oxidative stress, and tightly regulated by Kelch‐like ECH‐associated protein 1 (Keap1). In this study, we found that auranofin and paclitaxel combination treatment increased TUNEL positive apoptotic cells and enhanced the DNA damage marker γ‐H2AX in MCF‐7 and MDA‐MB‐231 breast cancer cells. The immunoblotting analysis revealed the combination of auranofin and paclitaxel significantly increased the FOXO3 expression in a concentration dependent manner. Further we observed that auranofin and paclitaxel treatment prevents the translocation of Nrf2 in a concentration dependent manner. The increased FOXO3 expression might be involved in the cytoplasmic degradation of Nrf1‐Keap1 complex. Further, the molecular docking results confirm auranofin act as the agonist for Foxo3. Therefore, the present results suggest that auranofin sensitize the breast cancer cells to paclitaxel via regulating FOXO3/Nrf2/Keap1signaling pathway. Significance Statement: The present results show that auranofin enhances paclitaxel induced TUNEL positive apoptotic cells. Further, auranofin treatment increases FOXO3 which in turn inhibit the dissociation of Nrf2 and Keap1 in both MDA‐MB‐231 and MCF‐7 cell lines. Therefore, the present results clearly illustrate the chemosensitizing property of auranofin via regulating FOXO3/Nrf2/Keap1 signaling pathway in the breast cancer cells. Auranofin is already a Food and Drug administration approved drug and it could be considered for the clinical applications after preclinical experimentation. [ABSTRACT FROM AUTHOR]

The intrinsic redox status of cancer cells limits the efficacy of chemotherapeutic drugs. Auranofin, a Food and Drug Administration‐approved gold‐containing compound, documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel‐sensitizing effect of auranofin by targeting redox balance in the MDA‐MB‐231 and MCF‐7 breast cancer cell lines. Auranofin treatment depletes the activities of superoxide dismutase, catalase, and glutathione peroxidase and alters the redox ratio in the breast cancer cell lines. Furthermore, it has been noticed that auranofin augmented paclitaxel‐mediated cytotoxicity in a concentration‐dependent manner in both MDA‐MB‐231 and MCF‐7 cell lines. Moreover, auranofin increased the levels of intracellular reactive oxygen species (observed using 2, 7‐diacetyl dichlorofluorescein diacetate staining) and subsequently altered the mitochondrial membrane potential (rhodamine‐123 staining) in a concentration‐dependent manner. Further, the expression of apoptotic marker p21 was found to be higher in auranofin plus paclitaxel‐treated breast cancer cells compared to paclitaxel‐alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA‐MB‐231 and MCF‐7 breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy. Significance statement: In this study, auranofin, a Food and Drug Administration‐approved drug, has been repurposed for anticancer activity. The results illustrate that auranofin improved paclitaxel‐mediated cytotoxicity in breast cancer cell lines. The auranofin treatment altered the intracellular redox balance in the breast cancer cells, which contributes to paclitaxel‐mediated cell cycle arrest and subsequent apoptotic cell death. Thus, the present results illustrate the chemosensitizing property of auranofin in breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Synthesis of β -CDP/QD NCs using epichlorohydrin linker to overcome. P-glycoprotein (P-gp) mediated MDR in cancer cells. The β -CDP/QD NCs enter the MDR cancer cells through endocytosis. The QCT released from the nanocarrier enhances the intracellular availability of DOX via blocking the drug efflux function of P-gp. [Display omitted] • The β -CDP/QD NCs were successfully synthesized by the freeze-dried method. • Spectroscopic and microscopic studies evaluate the encapsulation of drugs in polymer. • The β -CDP/QD NCs show burst and sustained release of quercetin and doxorubicin. • β -CDP/QD NCs show enhanced apoptotic cell death in MDR cancer cells. In this study, we prepared a β -cyclodextrin polymer (β -CDP) co-loaded quercetin (QCT) and doxorubicin (DOX) nanocarrier (β -CDP/QD NCs) by freeze-dried method to combat P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in KB-ChR 8–5 cancer cells. Various microscopic and spectroscopic techniques were employed to characterize the prepared nanocarrier. The molecular docking studies confirm the effective binding interactions of QCT and DOX with the synthesized β -CD polymer. The in vitro drug release study illustrates the sustainable release of DOX and QCT from the β -CDP nanocarrier. Further, we noticed that the QCT released from the β -CDP nanocarrier improved the intracellular availability of DOX via modulating P-gp drug efflux function in KB-ChR 8–5 cells and MCF-7/DOX cancer cells. Cell uptake results confirmed the successful internalization of DOX in KB-ChR 8–5 cells compared with free DOX. Cell-based assays such as nuclear condensation, alteration in the mitochondrial membrane potential (MMP), and apoptosis morphological changes confirmed the enhanced anticancer effect of β -CDP/QD NCs in the resistant cancer cells. Hence, QCT and DOX co-loaded β -CDP may be considered effective in achieving maximum cell death in the P-gp overexpressing MDR cancer cells. [ABSTRACT FROM AUTHOR]