Journal
FRONTIERS IN PHARMACOLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2021.714628
Keywords
TNBC; cancer stem cell; network pharmacology; Xihuang pill; naringenin
Categories
Funding
- National Natural Science Foundation of China [81904206, 81974571]
- Guangdong Natural Science Foundation [2017A030313719]
- Foundation Project of Guangzhou University of Traditional Chinese Medicine [XKP2019002]
- Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources [2060302]
- Hainan health industry scientific research project [20A200121, 20A200525]
- [20A200121and 20A200525]
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Xihuang pill, a commonly used adjuvant drug for cancer patients in China, has shown satisfactory effects in treating breast cancer, especially triple-negative breast cancer. The study revealed that Xihuang pill can reduce the stemness of TNBC cells by regulating naringenin and the NR3C2 gene, thus enhancing the synergistic effect with paclitaxel.
Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell-related genes were identified. The drug-herb-active compound-target gene-disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene.
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