Abstract
Tanshinone IIA (Tan IIA) was mainly used for cardiovascular disease treatment. Recent studies have demonstrated the role of Tan IIA for tumor treatment, but its mechanism remains unclear. At the first, the inhibitory effect of Tan IIA on 4T1 breast cancer cells was determined by CCK8 and colony formation assay. Then, a 4T1 BALB/c model of breast cancer was established to evaluate the anti-cancer effect of Tan IIA in vivo. Flow cytometry analysis and the TUNEL test were used to detect cell apoptosis in vitro and in vivo, respectively. The related targets and mechanisms of Tan IIA were predicted through network-based systems biology. At last, molecular docking and the molecular biological techniques were used to evaluate the predicted targets. Tan IIA displayed encouraging inhibitory influences on 4T1 cells after incubation for 24 h and showed a half-maximal inhibitory concentration (IC50) of 49.78 μM after 48-h incubation. After 23 days of treatment, the relative tumor volumes in the Tan IIA group were 65.53% inhibited compared with the control group. Furthermore, Tan IIA induced 4T1 cell apoptosis both in vivo and in vitro. The possible targets of Tan IIA for TNBC treatment were predicted with network-based systems biology, and results showed that TP53, NF-κB, AKT, MYC, and BCL-2 were the hub targets. The mechanism against breast cancer may be based on the P53 signaling pathway, the PI3K/Akt pathway, the MAPK signaling pathway, and the mTOR signaling pathways. Molecular docking analysis reveals that Tan IIA has a high affinity for p53, Bcl-2, and NF-κB1; the binding energies were − 6.92, − 6.07, and − 6.28 kcal/mol, respectively. The predicted proteins were further validated using Western blotting. Increased expression of phosphorylated p53 and p53 and decreased expression of Bcl-2 were found in Tan IIA-treated 4T1 cells. Tan IIA is potentially effective for the treatment of 4T1 breast cancer, and the molecular mechanism may be through enhancing the activity of p53 and decreasing Bcl-2 to suppress proliferation and promote apoptosis.
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The datasets generated and/or analyzed during the current study are not publicly available due to subsequent experiments that have not been completed but are available from the corresponding author on reasonable request.
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This work was supported by the National Natural Science Foundation of China (Grant No. 81903934) and the National Natural Science Foundation of China (Grant No. 81473441).
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JH and XW conceived and designed research. JL, CZ, and SL conducted experiments and wrote the manuscript. XW analyzed data. All authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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Liu, J., Zhang, C., Liu, S. et al. Tanshinone IIA promotes apoptosis by downregulating BCL2 and upregulating TP53 in triple-negative breast cancer. Naunyn-Schmiedeberg's Arch Pharmacol 396, 365–374 (2023). https://doi.org/10.1007/s00210-022-02316-1
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DOI: https://doi.org/10.1007/s00210-022-02316-1