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

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.

Characteristics of the Cytotoxicity of Taraxacum mongolicum and Taraxacum formosanum in Human Breast Cancer Cells

“…T. of fi cinale is distributed worldwide and is the subject of more than 70% of pharmacological references to Taraxacum . Phytochemical investigations have revealed that dandelion contains chicoric acid, flavonoids, lactones, phenolics, polysaccharides, sesquiterpenes, and triterpenes [ 10 , 11 , 14 , 15 , 17 , 20 ]. Importantly, several bioactive compounds extracted from various Taraxacum species, including T. mongolicum and T. formosanum , remain to be identified.…”

“…The identification of active compounds and working mechanisms against diseases could enable these herbal traditional medicines to emerge as commercial herbs. However, only a small proportion of dandelion species are currently being scientifically studied [ 10 , 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. The genus Taraxacum has been used to treat breast cancer in traditional folk medicine [ 15 , 17 , 18 , 19 , 20 , 21 ].…”

“…However, only a small proportion of dandelion species are currently being scientifically studied [ 10 , 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. The genus Taraxacum has been used to treat breast cancer in traditional folk medicine [ 15 , 17 , 18 , 19 , 20 , 21 ]. Moreover, it was recently demonstrated that cell apoptosis related to the PERK/p-eIF2α/ATF4/CHOP endoplasmic reticulum stress axis [ 10 ] and suppression of IL-10/STAT3/PD-L1 signaling accounted for the anticancer effect of T. mongolicum ethanolic extract against TNBC [ 18 ], and the ethanolic extract also exhibited estrogenic activity [ 21 ].…”

Signaling Pathways and Natural Compounds in Triple-Negative Breast Cancer Cell Line

“…Luteolin significantly inhibited tumor cell migration to reduce VEGF levels and block VEGF receptors, with IC 50 of 10 µM in vitro and in vivo [161]. In addition, luteolin from Taraxacum officinale extract can inhibit Nrf2 in breast cancer stemness (Cripto1, CD44, ALDH1, ABCG2, NANOG, OCT4, and Sirt3) and chemoresistance, with IC 50 value 1 µM in an MDA-MB-231 cell line in vitro study [162].…”

Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets

“…On the other hand, the activity of NRF2 is the key to chemotherapy resistance in MCF7 BC cells [119] . The chemotherapeutic agents, such as luteolin, enhanced the chemosensitivity through downregulating the NRF2 expression [120] , suggesting that a low NRF2 signature may be key to cellular sensitivity to both chemical carcinogenic stimuli and the cytotoxicity of commonly used chemotherapeutic drugs in established BC [121] .…”