Hinokiflavone induces apoptosis and inhibits migration of breast cancer cells via EMT signalling pathway

Abstract

Hinokiflavone is a natural product, isolated from Selaginella P. Beauv, Juniperus phoenicea and Rhus succedanea. Even though hinokiflavone was reported to possess cytotoxicity to many cancer cells, and has potential in cancer treatment, the antiproliferation and anti-metastasis efficacy of hinokiflavone on human breast cancer cells has not a further research. In this study, we investigated the anti-cancer activity of hinokiflavone in human breast cancer cells in vitro and in vivo. Hinokiflavone exhibited a time-and dose-dependent manner apoptosis induction by upregulating expression of Bax and downregulating Bcl-2 in breast cancer cells. Furthermore, hinokiflavone significantly inhibited the migration and invasion of breast cancer cells by impairing the process of epithelial-to-mesenchymal transition. In addition, the tumour growth was distinctly inhibited by treatment of hinokiflavone in a xenograft tumour mouse model of MDA-MB-231 cells. Immunohistochemical analysis of tumour sections showed that MMP-2 + cells and Ki-67 + cells were remarkably decreased in tumour tissues of mice after treatment of hinokiflavone, indicating that hinokiflavone inhibits not only proliferation but also metastasis of breast cancer cells.Our study suggested that hinokiflavone can be a potential drug to breast cancer.Significance of the study Hinokiflavone significantly inhibited proliferation and induced apoptosis in breast cancer cells. In addition, hinokiflavone remarkably inhibited migration and invasion of breast cancer cells via EMT signalling pathway.It is worth noting that hinokiflavone possesses anti-tumour effect in tumour mouse xenograft model of breast cancer. Overall, our results indicated that hinokiflavone may be a potential anticancer drug for breast cancer treatment.

Hinokiflavone and Related C–O–C-Type Biflavonoids as Anti-cancer Compounds: Properties and Mechanism of Action

“…The drug-induced modulation of the Bax/Bcl-2 expression ratio (up-regulation of Bax, down-regulation of Bcl-2), associated with a release of cytochrome c and caspases activation has been clearly evidenced using colon [ 53 ], hepatocellular [ 55 ] and breast [ 56 ] cancer cells. In addition, in the case of hepatocellular carcinoma (HCC), HNK was found to inhibit the activation of NFκB (nuclear factor kappa B) signaling, thereby suppressing the expression of several NFκB-target anti-apoptotic genes, and thus reinforcing the direct proapoptotic effect of the compound via up-regulation of phospho-JNK [ 55 ].…”

“…In the study using a breast cancer model (MDA-MB-231), the authors pointed out the induction of apoptosis as well as a marked anti-metastatic effect. HNK inhibited migration and invasion of breast cancer cells via a modulation of the epithelial‐to‐mesenchymal transition (EMT), specifically through an up‐regulation of the expression level of E‐cadherin and down‐regulation of N‐cadherin [ 56 ]. HNK thus displays both antiproliferative and anti-metastatic properties.…”

“…In all three cases, the drug significantly slowed down the tumor growth but did not stopp the growth. The effect was relatively modest with the MDA-MB-231 breast cancer model, with a reduction of the tumor volume by 30–40% when HNK was given (intraperitoneal injection) at 20–40 mg/kg [ 56 ]. A slightly better effect was obtained when using the CT26 colon cancer model, with a reduction of the tumor volume reaching about 50% when the drug was used at 50 mg/kg [ 53 ].…”

“…This is the case for HNK which down-regulates the expression of MMP-2 and -9 in A375 and B16 melanoma cells, so as to reduce the invasion/migration capacities of these tumor cells [ 54 ]. A down-regulation of MMP-2 was also observed in HNK-treated breast cancer cells [ 56 ]. The downregulation of MMPs by HNK can be explained by the modulation of the ERK/NFκB signaling pathway [ 25 ].…”

“…It is known that SENP1 regulates the migration and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma [ 91 ]. Therefore, inhibition of SNEPs by HNK could explain the observed effects mentioned above, such as the drug-induced modulation of the EMT and reduction of metastasis [ 56 ].

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