Abstract
Background and purpose: Metastasis is an important cause of death in breast cancer patients. Anti-metastatic agents are urgently needed since standard chemotherapeutics cannot diminish the metastatic rate. Actein, a cycloartane triterpenoid, has been demonstrated to exhibit anti-angiogenic and anti-cancer activities. Its anti-metastatic activity and underlying mechanisms were evaluated in the present study.Methods: The effects of actein on the proliferation, cell cycle phase distribution, migration, motility and adhesion were evaluated using two human breast cancer cell lines, MDA-MB-231 (estrogen receptor-negative) and MCF-7 cells (estrogen receptor-positive) in vitro. Western blots and real-time PCR were employed to examine the protein and mRNA expression of relevant signaling pathways. A human metastatic breast cancer cell xenograft model was established in transparent zebrafish embryos to examine the anti-migration effect of actein in vivo.Results: In vitro results showed that actein treatment significantly decreased cell proliferation, migration and motility. Furthermore, actein significantly caused G1 phase cell cycle arrest and suppressed the protein expression of matrix metalloproteinases of MDA-MB-231 cells. In addition, actein inhibited breast cancer cell adhesion to collagen, also reduced the expression of integrins. Actein treatment down-regulated the protein expression of epidermal growth factor receptor (EGFR), AKT and NF-κB signaling proteins. In vivo results demonstrated that actein (60 μM) significantly decreased the number of zebrafish embryos with migrated cells by 74% and reduced the number of migrated cells in embryos.Conclusion: Actein exhibited anti-proliferative, anti-adhesion and anti-migration activities, with the underlying mechanisms involved the EGFR/AKT and NF-kappaB signalings. These findings shed light for the development of actein as novel anti-migration natural compound for advanced breast cancer.
Highlights
Breast cancer is currently the second most lethal cancer in women, with continuous increase in incidence in recent decades (Torre et al, 2017)
Extracellular matrix (ECM)-associated proteases, cell surface protein involved in AKT/NF-Kb signaling were determined upon actein treatment in MDA-MB-231 breast cancer cells
MDA-MB231 cells were used in the studies of underlying intracellular mechanisms of the anti-migration effect of actein since ERnegative breast cancer cells are more prone to metastasis than estrogen receptor (ER)-positive cells
Summary
Breast cancer is currently the second most lethal cancer in women, with continuous increase in incidence in recent decades (Torre et al, 2017). Extracellular matrix (ECM)-associated proteases, cell surface protein involved in AKT/NF-Kb signaling were determined upon actein treatment in MDA-MB-231 breast cancer cells. Another compound deoxyactein (DA), from Cimicifuga with similar structure of actein was used as control compound. DA only exerts very minor effect on MCF-7 cell growth that could be ignored when compared to the potent effect of actein (Einbond et al, 2004) It was regarded as an inactive analog compound and included in the in vitro cytotoxicity tests on MDA-MB-231 cells for comparison with actein. Its anti-metastatic activity and underlying mechanisms were evaluated in the present study
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