Inhibitory Effects of Tangeretin, A Citrus Peel-Derived Flavonoid, on Breast Cancer Stem Cell Formation through Suppression of Stat3 Signaling.

Yu-Chan Ko,Hack Sun Choi,Dong-Sun Lee,Su-Lim Kim,Ji-Hyang Kim,Ren Liu,Bong-Sik Yun

doi:10.3390/molecules25112599

Abstract

Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified compound was identified as tangeretin by using nuclear magnetic resonance (NMR). Tangeretin inhibited cell proliferation, CSC formation and tumor growth, and modestly induced apoptosis in CSCs. The frequency of a subpopulation with a CSC phenotype (CD44+/CD24−) was reduced by tangeretin. Tangeretin reduced the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3). Our results in this study show that tangeretin inhibits the Stat3 signaling pathway and induces CSC death, indicating that tangeretin may be a potential natural compound that targets breast cancer cells and CSCs.

Highlights

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among females [1]
We showed that tangeretin had antiproliferative effects on breast cancer cells and reduced Breast cancer stem cells (BCSCs)
A Cancer stem cells (CSCs)-inhibiting compound derived from citrus was purified by bioassay-guided isolation, as shown in Figure 1A and Supplementary Figure S10

Summary

Introduction

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among females [1]. Triple-negative breast cancer (TNBC) accounts for approximately 10–15% of all diagnosed breast cancers [2], and is defined as ER-, PR- and HER2-negative breast cancer. Women with TNBC have a high risk of recurrence within three years of diagnosis, and the mortality rate is increased for five years after diagnosis [3]. Cancer stem cells (CSCs) are relatively resistant to chemotherapy, radiotherapy and hormone therapy [4]. CSCs have functional roles in self-renewal and differentiation [5]. CSCs are responsible for the processes of cancer initiation, metastasis and cancer relapse [6]. Breast CSCs may contribute to drug resistance and relapse [7].

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