Chestnut Leaf Extract Increases Sensitivity of Breast Cancer Stem Cells to Paclitaxel by Inhibiting Nrf2 Activity

Abstract

Tumor cells consist of various clonal subpopulations, thus displaying heterogeneous tumorigenicity. Only a subset of tumor cells, called cancer stem cells (CSCs), uniquely possesses high potency to initiate tumorigenesis and to locally or systematically disseminate tumor cells. Based on their properties, CSCs come to be a critical target for the development of chemotherapeutic strategies. Interestingly, it has been known that Nrf2‐mediated antioxidant enzymes are highly expressed in CSCs, which may be responsible for lowering the intracellular ROS level and the vulnerability to chemotherapeutic agents. As anticancer drugs usually utilize ROS as an arsenal for killing cancer cells, we hypothesized that suppression of Nrf2 activity may increase susceptibility of CSCs to anticancer drugs, improving their therapeutic efficacy. Our findings demonstrate that MCF‐7 CSCs having a CD44high/CD24low phenotype formed mammospheres and highly expressed Nrf2 compared to original MCF‐7 cells. In addition, total 89 kinds of Korean edible plant extracts were screened for the inhibitory activity against Nrf2 signaling pathway using an ARE‐luciferase assay system. Among these samples, Chestnut (Castanea crenata) leaf extract dramatically decreased nuclear translocation of Nrf2 and its downstream protein expression of antioxidant enzymes in MCF‐7 CSCs, and also attenuated the resistance to paclitaxel. These findings suggest that Chestnut leaf extract or its constituents could be utilized to increase therapeutic efficacy of anticancer agents through inhibition of Nrf2 signaling pathway.Support or Funding InformationThis study was supported by the National Research Foundation (Grant No. R2014R1A2A2A01005773, funded by the Ministry of Science, ICT and Future Planning; Grant No. 2013R1A1A2013362, funded by the Ministry of Education) Republic of Korea.