Suppression of Nrf2 Activity by Chestnut Leaf Extract Increases Chemosensitivity of Breast Cancer Stem Cells to Paclitaxel.

Yaejin Woo,Jisun Oh,Jong-Sang Kim

doi:10.3390/nu9070760

Abstract

Due to metastatic potential and drug resistance, cancer stem cells (CSCs) have become a critical target for the development of chemotherapeutic agents. Recent studies showed that CSCs highly express NF-E2-related factor 2 (Nrf2)-mediated antioxidant enzymes and thereby retain relatively low levels of reactive oxygen species (ROS). Since anticancer agents usually utilize ROS as an arsenal for killing cancer cells, we hypothesized that inhibition of Nrf2 activity could increase the sensitivity of CSCs to anticancer drugs, and thus enhancing their therapeutic efficacy. We found that MCF-7-derived CSCs with a CD44high/CD24low phenotype formed mammospheres and highly expressed Nrf2 compared to the adherent parental MCF-7 cells. In a separate experiment, we screened 89 different edible plant extracts for inhibitory activity against the Nrf2 signaling pathway by using an antioxidant response element (ARE)-luciferase assay system. Among those extracts, Castanea crenata (chestnut) leaf extract significantly decreased the nuclear translocation of Nrf2 and protein expression of antioxidant enzymes in MCF-7-derived CSCs. The combined treatment of the CSCs with chestnut leaf extract and paclitaxel resulted in more effective cell death than the treatment with paclitaxel alone. These findings suggest that the chestnut leaf extract or its constituents could increase the susceptibility of breast CSCs to an anticancer drug, paclitaxel, through inhibition of the Nrf2 signaling pathway, and could be utilized as an adjuvant for chemotherapy.

Highlights

The cells within a tumor are heterogeneous in tumorigenic potential
Breast cancer stem cells (CSCs) possessing these capabilities are reported to be the seed of breast cancer in humans and animal models [4,5]; the cell population is mainly positive for cluster of differentiation (CD) 44 (CD44) and negative for CD24 [6,7,8] and generally cultivated as mammospheres [6,7,8,9]
In an effort to improve adjuvant chemotherapy efficacy, we screened various edible plant extracts for an inhibitory effect against NF-E2-related factor 2 (Nrf2)-mediated antioxidant responses and found that chestnut leaf extract was most effective in inhibiting Nrf2 signaling pathway whose upregulation was associated with reduced efficacy of anticancer drugs including paclitaxel

Summary

Introduction

It is believed that a single clone within the tumor hierarchically diversifies into multiple subclones and the unique subset of tumor cells, called cancer stem cells (CSCs), is capable of self-renewing unlimitedly, differentiating into the tumor progeny, and reinitiating the tumor [1,2,3]. Breast CSCs possessing these capabilities are reported to be the seed of breast cancer in humans and animal models [4,5]; the cell population is mainly positive for cluster of differentiation (CD) 44 (CD44) and negative for CD24 [6,7,8] and generally cultivated as mammospheres [6,7,8,9]. Based on the evidence that the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) is constitutively activated in CSCs, it is appreciated

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