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.