Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/β‐catenin signaling cascades and reversal of epithelial–mesenchymal transition

Abstract

Cardamonin (CD), an active chalconoid, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of CD for the treatment of triple negative breast cancer (TNBC) is unclear. This study aims to examine the cytotoxic effects of CD and investigate the underlying mechanism in human TNBC cells. The results show that CD exhibits cytotoxicity by inducing apoptosis and cell cycle arrest in TNBC cells via modulation of Bcl-2, Bax, cyt-C, cleaved caspase-3, and PARP. We find that CD significantly increases expression of the epithelial marker E-cadherin, while reciprocally decreasing expression of mesenchymal markers such as snail, slug, and vimentin in BT-549 cells. In parallel with epithelial-mesenchymal transition (EMT) reversal, CD down regulates invasion and migration of BT-549 cells. CD markedly reduces stability and nuclear translocation of β-catenin, accompanied with downregulation of β-catenin target genes. Using the TopFlash luciferase reporter assay, we reveal CD as a specific inhibitor of the Wnt3a-induced signaling. These results suggest the involvement of the Wnt/β-catenin signaling in the CD-induced EMT reversion of BT-549 cells. Notably, CD restores the glycogen synthase kinase-3β (GSK3β) activity, required for β-catenin destruction via the proteasome-mediated system, by inhibiting the phosphorylation of GSK3β by Akt. These occurrences ultimately lead to the blockage of EMT and the invasion of TNBC cells. Further antitumor activity of CD was tested in 4T1 (TNBC cells) induced tumor and it was found that CD significantly inhibited the tumor volume at dose of 5 mg/kg-treated mice. © 2016 BioFactors, 43(2):152-169, 2017.

SOX11 regulates apoptosis and cell cycle in hepatocellular carcinoma via Wnt/β‐catenin signaling pathway

“…In prostate cancer, glioma, non‐small‐cell lung cancer, and breast cancer, NLK was reported to suppress the proliferation and trigger the apoptosis of tumor cells . NLK exerts its function mainly through regulating Wnt/β‐catenin signaling pathway and androgen receptor signal pathways , both of which are considered to be oncogenic . In our study, SOX11‐induced NLK expression promoted the phosphorylation of TCF4 and thus blunted Wnt/β‐catenin cascade .…”

Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway

“…Cardamonin is a chalcone that has been extracted from several plants including Alpinia rafflesiana and was proven to possess cytotoxic properties against a wide variety of cancer cell lines such as A549, U266, HuCCA-1 and MOLT-3 [4]. Moreover, cardamonin's mode of action has been extensively studied, where it was found that it exerted its anticancer activity via modulation of several pathways such as Wnt/β-catenin and NF-κB signalling pathways [5][6]. However, there have been no studies performed on semi-synthetic analogues of cardamonin with anticancer properties, nor have there been any detailed investigations on the structureactivity relationship of cardamonin specifically.…”

Cardamonin induces immune responses and enhances survival rate in WEHI‐3 cell–generated mouse leukemia in vivo

“…AML mice have been used as a suitable animal model for examining the effects of agents (chemical compounds) on leukemia in vivo. Cardamonin presents biological activities including inducing apoptosis and inhibiting cell metastasis of cancer cells . However, currently no available information concerning the effects of cardamonin on immune responses and survival rate of AML mice in vivo were clarified.…”

“…Cardamonin is a kind of monomeric alkaloid, and it is extracted from a spicy, herbaceous plant, Alpinia conchigera Griff (Zingiberaceae family) and from the seed of Amomum subulatum . Cardamonin possesses the anti‐inflammation activity and anticancer activities via inhibiting the proliferation of tumor cells and reduces tumor growth in mice . It was reported that cardamonin exerted the antitumor effects on cancer cells through modulation of various signaling transductions including mTOR, STAT3, Wnt/β‐catenin, and NF‐κB signaling pathways .…”