Abstract
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.
Highlights
Traditional Chinese medicine (TCM), which is a significant part of alternative and complementary medicine, has been clinically used in Asia for more than a 1,000 years
As the results have shown, compared with the control groups, the viabilities of T47D, MCF-7, SKBR3, 4T1, and HCC1806 cells treated with serum containing Xihuang pill (XS) for 48 h were not significantly different (p > 0.05), which indicates that treatment with Xihuang pill cannot directly inhibit the proliferation of breast cells (Figure 2A)
Gene expression microarray data (GSE10885) identified a group of metastasis breast cancers (MBCs) that contrasted with the common breast tumor significantly expressed genes, which were highly related to triple-negative breast cancer (TNBC) stem cell–like properties (Hennessy et al, 2009)
Summary
Traditional Chinese medicine (TCM), which is a significant part of alternative and complementary medicine, has been clinically used in Asia for more than a 1,000 years As important TCM treatment methods, herbs and formulas have a positive clinical effect on cancer treatment, especially as adjuvant treatments, which cooperate with Western medicines to enhance the sensitivity of anticancer drugs and reduce side effects (Park et al, 2013; Meng et al, 2017; Huang et al, 2019). Qian et al reported that Xihuang pill combined with TP chemotherapy had a significant clinical effect in treating advanced breast cancer, where the total effective rate of the Xihuang pill adjuvant group was higher than that of the TP chemotherapy group (Qian et al, 2020). Wang et al reported that the Xihuang pill–combined group has a satisfactory effect in the treatment of advanced breast cancer with improvements in the survival rate and life quality, which has a certain clinical application value (Wang and Yang, 2019). The current study of Xihuang pill remains in the basic stage, and the drug targets and pharmacological mechanisms of Xihuang pill in treating triple-negative breast cancer (TNBC) are still unclear
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