Abstract
BackgroundBreast cancer is the second leading cause of cancer related deaths among females worldwide. Berbamine (BER), a kind of bis-benzylisoquinoline alkaloid, has been used to treat clinical patients with inflammation and cancer for many years in China. The purpose of this study is to investigate the activity of BER against highly-metastatic human breast cancer and its molecular mechanisms of action.ResultsIn our study, we found that BER inhibits growth of highly-metastatic human breast cancer cell lines MDA-MB-231 and MDA-MB-435S cells dose-dependently and time-dependently. The sera from BER-treated rats suppress the growth of MDA-MB-231 cells. BER shows synergistic effects with some existing anticancer agents such as trichostatin A (TSA, the histone deacetylase inhibitor), celecoxib (the inhibitor of COX-2), and carmofur against the growth of MDA-MB-231 cells. BER also displays the strong activity of inducing apoptosis in both estrogen receptor-negative MDA-MB-231 cells and estrogen receptor-alpha-positive MCF-7 breast cancer cells, but not in normal human mammary epithelial cell line MCF10A. BER down-regulates anti-apoptotic protein Bcl-2 levels and up-regulates pro-apoptotic protein Bax expressions in MDA-MB-231 and MDA-MB-435S cells. BER also has synergistic effects with anticancer agents trichostatin A, celecoxib and/or carmofur on reducing Bcl-2/Bax ratios and VEGF secretions in MDA-MB-231 cells. In addition, BER significantly suppresses cell migration and invasion, as well as decreases pro-MMP-9/pro-MMP-2 activation in breast cancer cells. Furthermore, BER suppresses Akt and nuclear factor κB signaling by reducing the phosphorylation of c-Met and Akt, and inhibiting their downstream targets such as nuclear factor κB p-65, Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2 on protein and/or mRNA levels in breast cancer cells.ConclusionOur findings have showed that BER suppresses the growth, migration and invasion in highly-metastatic human breast cancer cells by possibly inhibiting Akt and NF-κB signaling with their upstream target c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2. BER has synergistic effects with anticancer agents trichostatin A, celecoxib and carmofur on inhibiting the growth of MDA-MB-231 cells and reducing the ratio of Bcl-2/Bax and/or VEGF expressions in the cancer cells. These findings suggest that BER may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer and other cancers.
Highlights
Breast cancer is the second leading cause of cancer related deaths among females worldwide
The sera collected at 1 h and 2 h from BER-treated rats significantly suppressed the growth of MDA-MB-231 cells after the cells were treated with the sera for 48 and 72 h, respectively, as compared with 0 h sera taken at 0 h from rats
BER showed the synergistic effects with the existing anticancer agents celecoxib, trichostatin A (TSA, the histone deacetylase inhibitor), and carmofur (KA or K) against the growth of MDA-MB-231 cells, which enhanced inhibitory rate of the cancer cell growth more than twice
Summary
Breast cancer is the second leading cause of cancer related deaths among females worldwide. In China, BER has been used to treat the clinical patients with inflammation and various cancers including breast cancer, hepatoma, leukemia for many years. BER-induced apoptosis and growth inhibition of human leukemia HL60 and K562 cell lines without cytotoxicity to normal hematopoietic cells [4,5,6]. We investigated the effects of BER on growth, migration and invasion of highly-metastatic human breast cancer cells and its molecular mechanisms of action. We showed that BER inhibited the growth, migration and invasion of the highly-metastatic human breast cancer cells as well as induced the apoptosis in the cancer cells. Such anti-cancer activities of BER involved suppression of Akt and NF-κB signaling and its upstream and downstream targets by reducing expressions of the related proteins and mRNA as well as proMMP-9/pro-MMP-2 activation in the cells
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