Abstract
Actein is a triterpene glycoside isolated from the rhizomes of Cimicifuga foetida (Chinese herb “shengma”) which could inhibit the growth of breast cancer cells. Nevertheless, the effect of actein on angiogenesis, which is an essential step for tumor growth and metastasis, has never been reported. Hence, this study aimed to investigate the in vitro and in vivo effects of actein on angiogenesis using human microvascular endothelial cells (HMEC-1), matrigel plug and tumor-bearing mouse models. Our results showed that actein significantly inhibited the proliferation, reduced the migration and motility of endothelial cells, and it could suppress the protein expressions of VEGFR1, pJNK and pERK, suggesting that JNK/ERK pathways were involved. In vivo results showed that oral administration of actein at 10 mg/kg for 7 days inhibited blood vessel formation in the growth factor-containing matrigel plugs. Oral actein treatments (10–15 mg/kg) for 28 days resulted in decreasing mouse 4T1 breast tumor sizes and metastasis to lungs and livers. The apparent reduced angiogenic proteins (CD34 and Factor VIII) expressions and down-regulated metastasis-related VEGFR1 and CXCR4 gene expressions were observed in breast tumors. Our novel findings provide insights into the use of actein for development of anti-angiogenic agents for breast cancer.
Highlights
Chemotherapy agents to inhibit cancer cell growth[14,15], as well as induced calcium release and modulated the nuclear factor (NF)-κB and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) pathways[16]
We reported for the first time that actein, the active compound found in Cimicifuga species, possessed anti-angiogenic and immunomodulatory effects in a murine breast tumor-bearing model
Actein is a bioactive triterpene glycoside isolated from Cimicifuga species and has been demonstrated for its inhibitory activities on the growth of breast cancer cells[8,13] as well as of osteoblastic cells[17,18]
Summary
Chemotherapy agents to inhibit cancer cell growth[14,15], as well as induced calcium release and modulated the NF-κB and Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK) pathways[16]. The activities of actein on angiogenesis and tumor growth in tumor-bearing animal models have never been reported. Different responsible angiogenic pathways among different molecular subtypes of breast cancer were investigated in preclinical and clinical studies over the last decade[32]. Being reported as an anti-tumor natural compound, actein has not been studied for its activity on angiogenesis and in breast tumor-bearing animal models. We reported for the first time that actein, the active compound found in Cimicifuga species, possessed anti-angiogenic and immunomodulatory effects in a murine breast tumor-bearing model. The VEGFR1, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways were involved in actein’s anti-angiogenic activities, which might subsequently inhibit the orthotopic tumor growth and metastasis of tumor cells in mice. The beneficial role of oral administered actein in immune responses of breast tumor-bearing mice was firstly revealed in the present study
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