Luteolin Inhibits Breast Cancer Stemness and Enhances Chemosensitivity through the Nrf2-Mediated Pathway.

Kuen-Jang Tsai,Ming-Wei Lin,Chun-Lin Chen,Tsung-Hua Hsieh,Hsin-Yi Tsai,Chin-Chuan Tsai,Lulekiwe Mbuyisa,Yaw-Bin Huang,Tai-Yu Chen

doi:10.3390/molecules26216452

Abstract

Cancer stem cells (CSCs) are subpopulations of tumor masses with unique abilities in self-renewal, stemness maintenance, drug resistance, and the promotion of cancer recurrence. Recent studies have suggested that breast CSCs play essential roles in chemoresistance. Therefore, new agents that selectively target such cells are urgently required. Reactive oxygen species (ROS)-producing enzymes are the reason for an elevated tumor oxidant status. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor, which upon detecting cellular oxidative stress, binds to the promoter region of antioxidant genes. By triggering a cytoprotective response, Nrf2 maintains cellular redox status. Cripto-1 participates in the self-renewal of CSCs. Herein, luteolin, a flavonoid found in Taraxacum officinale extract, was determined to inhibit the expressions of stemness-related transcriptional factors, the ATP-binding cassette transporter G2 (ABCG2), CD44, aldehyde dehydrogenase 1 activity as well as the sphere formation properties of breast CSCs. Furthermore, luteolin suppressed the protein expressions of Nrf2, heme oxygenase 1 (HO-1), and Cripto-1 which have been determined to contribute critically to CSC features. The combination of luteolin and the chemotherapeutic drug, Taxol, resulted in enhanced cytotoxicity to breast cancer cells. These findings suggest that luteolin treatment significantly attenuated the hallmarks of breast cancer stemness by downregulating Nrf2-mediated expressions. Luteolin constitutes a potential agent for use in cancer stemness-targeted breast cancer treatments.

Highlights

This article is an open access articleChemotherapy is the treatment of choice for breast cancer, but available therapeutics have limited efficacy
We evaluated the potential roles of luteolin in cancer stemness and chemoresistance inhibition in triple-negative breast cancer cells
Our results demonstrated that luteolin suppressed Nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), Sirtuin 3 (Sirt3), and Cripto-1 expression in MDA-MB-231 cells

Summary

Introduction

This article is an open access article. Chemotherapy is the treatment of choice for breast cancer, but available therapeutics have limited efficacy. Cancer stem cells (CSCs) are subpopulations of tumor masses with unique abilities in self-renewal, stemness maintenance, drug resistance, and the promotion of cancer recurrence [1,2,3]. Recent studies have suggested that CSCs play essential roles in chemoresistance [4]. In the context of breast cancer treatment, including the development distributed under the terms and conditions of the Creative Commons. Of precision medical treatments, CSCs are a potential novel therapeutic target [5,6]. CSCs in breast cancers possess similar features to normal stem cells, which are involved in the production of antioxidants [7]. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is the key transcription factor regulating oxidative homeostasis, which upon detecting cellular oxidative stress, binds to the promoter region of antioxidant genes to promote the expression of antioxidant enzymes

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Conclusion