Tanshinone IIA Promotes Apoptosis by Down-Regulating BCL2 and Up-Regulating TP53 in Triple-Negative Breast Cancer

Abstract Background/Objective: Tanshinone IIA, which is mainly used for the treatment of cardiovascular diseases, has been shown to inhibit the progression of a variety of cancers in recent years. In this study, we showed that tanshinone IIA could inhibit the proliferation of triple-negative breast cancer cells and promote their apoptosis. However, the specific mechanisms were not clear. Our research aims to clarify its mechanism. Method: At the first, the effects of tanshinone IIA on cell viability of triple-negative breast cancer cell lines were analyzed. Then a mouse transplanted tumor model was used to study the anti-cancer effect in vivo. The related targets and mechanisms of tanshinone IIA were predicted through network-based systems biology and molecular docking analysis. At last, molecular docking and the molecular biological techniques were used to evaluate the predicted target. Results: Tanshinone IIA could inhibit the cell proliferation after incubation for 24 h. At a concentration of 50 µM, Tanshinone IIA could half-inhibit the proliferation of 4T1 cells. Consistent with the results of the cell viability assays, Tan IIA induced the cancer cell apoptosis and resulted in a significant reduction in tumor volume. Then we analyzed the possible mechanisms with network-based systems biology, and predicted TP53, NF-κB, AKT, MYC and BCL-2 were the hub targets of Tan IIA for triple-negative breast cancer. P53 signaling pathway, PI3K/Akt pathway, the MAPK signaling pathway and the mTOR signaling pathways were the possible involved mechanisms. Using molecular docking analysis, we found Tan IIA has a high affinity for p53, Bcl-2 and NF-κB1, the binding energy were − 6.92, -6.07 and − 6.28 kcal/mol, respectively. Through western blotting assays, we further found the p53 protein expression was increased while Bcl-2 protein was decreased after Tan IIA treatment. These results verified that Tan IIA promotes apoptosis by down-regulating BCL2 and up-regulating TP53 in triple-negative breast cancer.Conclusion: Our findings revealed the mechanism of Tan IIA in promoting apoptosis and inhibiting proliferation in triple-negative breast cancer cells, which provides a theoretical and experimental basis for further research into the anticancer effects of Tan IIA.