Abstract
The purpose of present study was to investigate the effect of dioscin on activity of adriamycin (ADR) in ADR-sensitive (MCF-7) and ADR-resistant (MCF-7/ADR) human breast cancer cells and to clarify the molecular mechanisms involved. Antiproliferation effect of ADR was enhanced by dioscin in MCF-7 and MCF-7/ADR cells. Dioscin significantly inhibited MDR1 mRNA and protein expression and MDR1 promoter and nuclear factor κ-B (NF-κB) activity in MCF-7/ADR cells. Additionally, inhibitor κB-α (IκB-α) degradation was inhibited by dioscin. Moreover, dioscin induced the formation of vacuoles in the cytoplasm and protein level of LC3-II in MCF-7 and MCF-7/ADR cells. Autophagy inhibitor 3-MA abolished the effect of dioscin on ADR cytotoxicity. Dioscin inhibited phosphorylation of PI3K and Akt, resulting in upregulation of LC3-II expression. In conclusion, dioscin increased ADR chemosensitivity by down-regulating MDR1 expression through NF-κB signaling inhibition in MCF-7/ADR cells. Autophagy was induced by dioscin to ameliorate the cytotoxicity of ADR via inhibition of the PI3K/AKT pathways in MCF-7 and MCF-7/ADR cells. These findings provide evidence in support of further investigation into the clinical application of dioscin as a chemotherapy adjuvant.
Highlights
Breast cancer is the most common cancer and the leading cause of cancer death among females worldwide, with an estimated 1.7 million cases and 521,900 deaths in 20121
Our studies have shown that dioscin restores the activity of the anticancer agent adriamycin (ADR) in multi-drug resistance (MDR) human leukemia K562/adriamycin cells and enhances methotrexate absorption by down-regulating MDR1 via a mechanism involving NF-κBsignaling inhibition[12,22]
We found that dioscin synergizes with ADR to decrease viability of ADR-resistant and ADR-sensitive MCF7 cells, which was different from K562 cells in our previous study[12]
Summary
Breast cancer is the most common cancer and the leading cause of cancer death among females worldwide, with an estimated 1.7 million cases and 521,900 deaths in 20121. Our studies have shown that dioscin restores the activity of the anticancer agent adriamycin (ADR) in MDR human leukemia K562/adriamycin cells and enhances methotrexate absorption by down-regulating MDR1 via a mechanism involving NF-κBsignaling inhibition[12,22]. Further study revealed that dioscin increased the activity of ADR in MCF-7 and MCF-7/ADR cells at nontoxic concentrations by down-regulating MDR involving the inhibition of the NF-κB signaling pathway in MCF-7/ADR cells, and worked by activation of autophagy via inhibition of PI3K/Akt pathway in both MCF-7 and MCF-7/ADR cells. These findings provided the potential use of dioscin in clinical application as MDR reversal agent
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