Abstract
Several reports have described the anti-cancer activity of arctigenin, a lignan extracted from Arctium lappa L. Here, we investigated the effect of arctigenin (ATG) on doxorubicin (DOX)-induced cell death using MDA-MB-231 human breast cancer cells. The results showed that DOX-induced cell death was enhanced by ATG/DOX co-treatment in a concentration-dependent manner and that this was associated with increased DOX uptake and the suppression of multidrug resistance-associated protein 1 (MRP1) gene expression in MDA-MB-231 cells. ATG enhanced DOX-induced DNA damage and decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the expressions of RAD51 and survivin. Cell death caused by ATG/DOX co-treatment was mediated by the nuclear translocation of apoptosis inducing factor (AIF), reductions in cellular and mitochondrial Bcl-2 and Bcl-xL, and increases in mitochondrial BAX levels. However, caspase-3 and -7 did not participate in DOX/ATG-induced cell death. We also found that DOX/ATG-induced cell death was linked with activation of the p38 signaling pathway and suppressions of the phosphorylations and expressions of Akt and c-Jun N-terminal kinase. Taken together, these results show that ATG enhances the cytotoxic activity of DOX in MDA-MB-231 human breast cancer cells by inducing prolonged p21 expression and p38-mediated AIF-dependent cell death. In conclusion, our findings suggest that ATG might alleviate the side effects and improve the therapeutic efficacy of DOX.
Highlights
Breast cancer is the major cause of cancer-related death among women
We evaluated changes in the gene expression of ATP-binding cassette (ABC) transporters multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein 1 (BCRP), because the effectiveness of chemotherapy is negatively associated with the expressions of these factors [24]
The present study demonstrates that ATG enhances the cytotoxic effect of DOX by increasing the cellular uptake of DOX and inducing the mitochondrial translocation of BAX, prolonged p21 induction, and the activation of p38, causing apoptosis inducing factor (AIF)-dependent cell death signaling
Summary
Breast cancer is the major cause of cancer-related death among women. many subtypes of breast cancer have been reported, they are generally classified as hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-overexpressing, and triple-negative breast cancer (TNBC) [1]. Because of the absence of HR and HER-2 in TNBC, non-targeting anti-cancer drugs such as paclitaxel, cyclophosphamide, and doxorubicin (DOX) are being used to treat the disease [5]. DOX is useful for the treatment of triple-negative breast cancer (TNBC), in practice its use is limited because of its serious side effects, which include cardiotoxicity, diarrhea, vomiting, hair loss, and nausea. 2. Reesnuhlatnsces the cytotoxic effect of DOX in MDA-MB-231 TNBC cells. Synergistic cytotoxic activity of ATG/DOX co-treatment was observed in MDA-MB-231 human triple negative breast cancer cells. Combination indices (CI) values quantitatively validated by Compusyn software was
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