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 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.
Breast cancer is the major cause of cancer-related death among women. Although 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]. Triple-negative breast cancer (TNBC) has a higher mortality rate than HR-positive or HER-2-overexpressing breast cancer because of its high rate of recurrence [
2,
3,
4]. Furthermore, 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 an anthracycline antibiotic and broad spectrum anti-cancer agent [
6,
7]. Although 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. Actually, the total dose of DOX administered must not exceed 450–500 mg/m
2 because of its cardiotoxicity [
6]. Furthermore, reductions in DOX dosage made to address its side effects reduce its therapeutic efficacy [
8].
Arctigenin (ATG) is a pharmaceutically active substance isolated from the seeds of
Arctium lappa L. (commonly called greater burdock), and several investigators have shown it has anti-viral, anti-inflammatory, anti-cancer, and immunomodulatory activities [
9,
10,
11,
12,
13]. The anti-cancer activity of ATG has been reported to due to the induction of apoptosis mediated by mitochondrial disruption and cell cycle arrest in breast, lung, bladder, gastric, hepatic, and colon cancer cells [
14,
15,
16,
17,
18]. In a recent study, we showed ATG suppressed metastatic potential and induced autophagic cell death by inhibiting estrogen receptor (ER) expression in MCF-7 human breast cancer cells [
19,
20]. Also, Wang et al. reported human non-small cell lung cancer (NSCLC) cells treated with ATG exhibited greater chemosensitivity to cisplatin-induced apoptotic cell death mediated by the down-regulation of survivin [
21].
Combination chemotherapies are being increasingly used to treat cancers to minimize toxicities and side effects based on the delivery of lower doses of the drugs responsible [
22,
23]. Numerous investigations have shown ATG has anti-cancer and anti-metastatic effects on different cancer cell types. Therefore, we assessed the effects of ATG/DOX co-treatment to determine whether ATG enhances the cytotoxic effect of DOX in MDA-MB-231 TNBC cells.
Although DOX is useful anti-cancer drug, its side effects severely restrict its use. However, reducing DOX dosages markedly mitigate these side effects. In the present study, we found the cytotoxic activity of DOX was significantly enhanced by co-treating it with ATG in MDA-MB-231 human triple-negative breast cancer cells and that DOX uptake was dose-dependently enhanced and MRP1 expression was dose-dependently suppressed in these cells (B and A,C). Furthermore, the presence of ATG synergistically increased DOX cytotoxicity (C). These results suggest that combinatorial ATG/DOX should be considered a potential treatment for triple-negative breast cancer that reduces the side effects of DOX.
In the present study, ATG co-treatment increased DOX-induced H2A.X phosphorylation, reversed DOX-induced survivin and RAD51 protein expressions, and increased DOX uptake by MDA-MB-231 cells (A,B). H2A.X phosphorylation is the result of DNA damage [
32,
33], and thus, we speculated that increased DOX-induced H2A.X phosphorylation by ATG reflects an increase in DNA, and that this enhanced MDA-MB-231 cell death (C). Cell death by DNA damage is primarily caused by a failure to repair DNA [
34,
35], and survivin and RAD51 play important roles in DNA repair [
36,
37]. Hence, the ATG/DOX-induced suppressions of survivin and RAD51 protein levels suggests increased cell death was due to an inability to repair DNA. Consequently, the present results suggest that ATG/DOX co-treatment-induced MDA-MB-231 cell death was associated with DNA damage and failure of the DNA repair system.
This entry is adapted from the peer-reviewed paper 10.3390/ijms21082997
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