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Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. P‐glycoprotein (P‐gp) one of the ATP‐binding cassette (ABC) transporters plays an important role in MDR. In this study, we examined the sensitizing property of andrographolide (Andro) to reverse MDR in the drug‐resistant KBChR 8‐5 cells. Andro exhibited increased cytotoxicity in a concentration‐dependent manner in the P‐gp overexpressing KBChR 8‐5 cells. Furthermore, Andro showed synergistic interactions with PTX and DOX in this drug‐resistant cells. Andro co‐administration enhanced PTX‐ and DOX‐induced cytotoxicity and reduced cell proliferation in the MDR cancer cells. Moreover, reactive oxygen species (ROS) were elevated with a decrease in the mitochondrial membrane potential (MMP) during Andro and chemotherapeutic drugs combination treatment in the drug‐resistant cells. Furthermore, Andro and PTX‐induced cell cycle arrest was observed in the drug‐resistant cell. We also noticed that the expression of ABCB1 and AKT were downregulated during Andro (4 µM) treatment. Furthermore, Andro treatment enhanced the expression of caspase 3 and caspase 9 in the combinational groups that support the enhanced apoptotic cell death in drug‐resistant cancer cells. Therefore, the results reveal that Andro plays a role in the reversal of P‐gp‐mediated MDR in KBChR 8‐5 cells which might be due to regulating ABCB1/AKT signaling pathway. Significance statement: ATP‐binding cassette (ABC) transporters‐mediated multidrug resistance (MDR) is a major hindrance during cancer treatment. Efflux mechanism of P‐glycoprotein (P‐gp) decreases bioavailability and efficacy of chemotherapeutic drugs. Already known inhibitors of P‐gp exhibit higher toxicity to the untargeted cells. Phytochemicals have great potential to reverse the MDR mechanism in cancer cells with less toxicity. Andrographolide (Andro), a phytochemical of Andrographis paniculata, enhanced the efficacy of the chemotherapeutic drugs and reverses drug resistance in MDR cancer cells. Therefore, Andro can be considered as a potent candidate to overcome MDR after preclinical and clinical validations. [ABSTRACT FROM AUTHOR]

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]

Ultraviolet radiation induces oxidative photoaging in the skin cells. In this study, we investigated the ability of andrographolide (ADP) to protect human dermal fibroblasts (HDFa) from UVB radiation‐induced oxidative stress and apoptosis. The HDFa cells were exposed to UVB (19.8 mJ/cm2) radiation in the presence or absence of ADP (7 μM) and then oxidative stress and apoptotic protein expression were analyzed. UVB exposure resulted in a significant decline in the activity of antioxidant enzymes and altered mitochondrial membrane potential (MMP). Furthermore, UVB‐irradiation causes increased intracellular reactive oxygen species (ROS) production, apoptotic morphological changes, and lipid peroxidation levels in the HDFa. Moreover, the pretreatment with ADP reduced the UVB‐induced cytotoxicity, ROS production, and increased antioxidant enzymes activity. Further, the ADP pretreatment prevents the UVB‐induced loss of MMP and apoptotic signaling in HDFa cells. Therefore, the present results suggest that ADP protects HDFa cells from UVB‐induced oxidative stress and apoptotic damage. Significance statement: Andrographolide (ADP) exhibits potent antioxidant in the in vitro free radical scavenging activity and it prevents UVB‐induced oxidative stress and apoptotic signaling in human dermal fibroblasts. Further, we suggest that the ADP pretreatment predominantly protects against UVB‐induced cytotoxicity, lipid peroxidation, antioxidant depletion, and apoptotic molecules. In this study, ADP possesses antioxidant effects; it could help to develop photoprotective and new sunscreen agents. [ABSTRACT FROM AUTHOR]