Abstract
The first-line chemotherapy drug adriamycin (ADM) is widely used for the treatment of breast cancer, but the acquired drug resistance and the normal tissue toxicity remain clinical challenges. Alteronol has been reported to exert wide-ranging anti-tumor activity. In this study, we firstly examined the synergistic anti-tumor effects and the underlying mechanisms of alteronol combined with ADM in breast cancer. We have found that the combination of alteronol and ADM significantly suppressed the expression levels of the cell cycle-related proteins (CDC2 and Cyclin B1) and induced cell cycle arrest at the G2/M phase, leading to cell proliferation inhibition in breast cancer 4T1 cells. Moreover, co-treatment of alteronol and ADM (i) remarkably activated p38 and JNK kinases, (ii) elevated ROS levels, (iii) triggered mitochondrial dysfunction, (iv) released cytochrome c into the cytoplasm, (v) upregulated apoptosis-related proteins, e.g., cleaved PARP, Bax, and cleaved caspase-3/9, and (vi) downregulated the expression of Bcl-2, followed by apoptosis. Furthermore, our in vivo studies showed that the low-dose combination of alteronol (2 mg/kg) and ADM (1 mg/kg) significantly inhibited tumor growth in tumor bearing mice, and the anti-tumor effect of the combination was the same as that of high-dose ADM (8 mg/kg). In addition, the low-dose combination group showed lower toxicities to major organs than the high-dose ADM group. Taken together, these data demonstrate that the low-dose combination of alteronol and ADM could notably improve the anti-tumor activity and have lower toxicities to major organs than those in high-dose ADM group.
Highlights
Breast cancer is one of the most frequently occurring malignant tumors in women, originating in the epithelial tissue of the breast (Ferlay et al, 2015; Torre et al, 2015)
To investigate whether alteronol could synergistically enhance the anti-proliferative activity of ADM in vitro, the cell survival of 4T1 cells was investigated by MTT assay after treatment with alteronol and/or ADM. 4T1 cells were firstly treated with different concentrations of alteronol (0∼11.36 μM) or ADM (0∼29.44 μM) for 24 and 48 h, respectively
We found that alteronol and ADM significantly inhibited the proliferation of
Summary
Breast cancer is one of the most frequently occurring malignant tumors in women, originating in the epithelial tissue of the breast (Ferlay et al, 2015; Torre et al, 2015). It is characterized by strong invasion, a high recurrence rate, easy metastasis and poor prognosis (Weigelt et al, 2005). Clinical data have demonstrated that the incidence of breast cancer has been increasing in Alteronol Enhances Adriamycin’s Antitumor Effect recent years. It has already threatened the public’s health and brought a tremendous economic burden to the society. ADM is recommended as the first-line chemotherapy for breast cancer treatment (Chen et al, 2017)
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