Tanshinone IIA induces apoptosis and autophagy in acute monocytic leukemia via downregulation of PI3K/Akt pathway

Acute myeloid leukemia (AML) is characterized by unrestrained proliferation of myeloid cells. In has been shown that tanshinone IIA (Tan IIA), exhibited anti-tumor activities on different types of cancers. However, the underlying mechanisms by which Tan IIA regulates apoptosis and autophagy in AML remain unclear. Thus, this study aimed to investigate the effects of Tan IIA on AML in vitro and in vivo. CCK-8 assay, EdU staining, flow cytometry, MDC staining, immunofluorescence, transwell migration and invasion assay were used to detect cell proliferation, apoptosis, autophagy, migration and invasion, respectively. In addition, western blotting was used to examine the protein levels of Bax, Bcl-2, active caspase-3, Beclin-1, Atg-5, p-mTOR and p-Akt in cells. Moreover, animal studies were performed to evaluate anti-tumor effect of Tan IIA on AML in vivo. The results revealed that Tan IIA significantly suppressed the growth of U937 cells in vitro and in vivo. Meanwhile, Tan IIA induced apoptosis in U937 cells via up-regulating the levels of active caspase-3 and Bax, and down-regulating BcI-2 in vitro and in vivo. In addition, Tan IIA inhibited the capacity of migration and invasion in U937 cells. Moreover, Tan IIA induced autophagy in U937 cells via upregulation of the expression of LC3 II, Atg5 and Beclin 1, which was further confirmed by MDC staining and immunofluorescence assays. For the first time, we have shown that autophagy inhibitor 3MA significantly enhanced Tan IIA-induced apoptosis in U937 cells. Furthermore, Tan IIA induced apoptosis and autophagy via downregulation of PI3K/Akt pathway in vitro and in vivo. Therefore, the accumulating evidences suggested that Tan IIA could be a potential agent for improving the symptoms of AML in the future.