Abstract
Chinese formulas have been paid increasing attention in cancer multidisciplinary therapy due to their multi-targets and multi-substances property. Here, we aim to investigate the anti-breast cancer and chemosensitizing function of Ai Du Qing (ADQ) formula made up of Hedyotis diffusa, Curcuma zedoaria (Christm.) Rosc., Astragalus membranaceus (Fisch.) Bunge, and Glycyrrhiza uralensis Fisch. Our findings revealed that ADQ significantly inhibited cell proliferation in both parental and chemo-resistant breast cancer cells, but with little cytotoxcity effects on the normal cells. Besides, ADQ was found to facilitate the G2/M arresting and apoptosis induction effects of paclitaxel. Network pharmacology and bioinformatics analysis further demonstrated that ADQ yielded 132 candidate compounds and 297 potential targets, and shared 22 putative targets associating with breast cancer chemoresponse. Enrichment analysis and experimental validation demonstrated that ADQ might improve breast cancer chemosensitivity via inhibiting caveolin-1, which further triggered expression changes of cell cycle-related proteins p21/cyclinB1 and apoptosis-associated proteins PARP1, BAX and Bcl-2. Besides, ADQ enhanced in vivo paclitaxel chemosensitivity on breast cancer. Our study not only uncovers the novel function and mechanisms of ADQ in chemosensitizing breast cancer at least partly via targeting caveolin-1, but also sheds novel light in utilizing network pharmacology in Chinese Medicine research.
Highlights
Breast cancer is the most common female malignancy and one of the leading causes of cancer-related deaths, with 252,710 new cases of invasive breast cancer and 40,610 breast cancer-related deaths diagnosed in women in the United States in 2017 (DeSantis et al, 2017)
We evaluated the influence of Ai Du Qing (ADQ) on the proliferation of breast cancer cell lines including MDA-MB-231 and MCF7, as well as their derived paclitaxel-resistant cell lines MDAMB-231/T and MCF-7/T
To determine the cytotoxic effects of ADQ on normal cells, we investigated its effects on human mammary epithelial cells (HUMECs) and human umbilical vein endothelial cells (HUVECs), and found that ADQ did not have cytotoxic inhibitory effects on both types of normal cells (Figures 1E,F)
Summary
Breast cancer is the most common female malignancy and one of the leading causes of cancer-related deaths, with 252,710 new cases of invasive breast cancer and 40,610 breast cancer-related deaths diagnosed in women in the United States in 2017 (DeSantis et al, 2017). Chemotherapy is one of the main therapeutic approaches for treating this disease, but it remains non-selectively toxic to normal tissues (Li et al, 2005). The activity of paclitaxel is primarily due to its inhibitory effects on microtubule assembly, which leads to arrest of the mitotic phase of the cell cycle and subsequent apoptosis. Paclitaxel application is still limited due to its systemic toxicity and acquired resistance (Janczar et al, 2017; Stage et al, 2018). Increasing attention has been paid to the synergistic effects of natural phytochemicals in enhancing the chemoresponse and relieving cytotoxic effects (Wang et al, 2014)
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