Cryptotanshinone inhibits the growth and invasion of colon cancer by suppressing inflammation and tumor angiogenesis through modulating MMP/TIMP system, PI3K/Akt/mTOR signaling and HIF-1 alpha nuclear translocation

The aim of this study was to evaluate the pharmacological effects of CPT on CT26 colon cancer cells in vivo and in vitro, and to reveal the potential mechanism. CPT suppressed the proliferation and growth of CT26 colon cancer in vitro and in vivo. CPT inhibited the invasion of CT26 cells in vitro, and decreased the protein expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 but increased those of tissue inhibitor of metallopeptidase-1 (TIMP-1) and TIMP-2 in vitro and in vivo. It also inhibited tumor cell-induced angiogenesis of endothelial cells in vitro and rat aortic ring angiogenesis ex vivo, and possibly by suppressing angiogenesis-associated factors. CPT suppressed the expressions of inflammatory factors in vivo and in vitro. Mechanism studies showed that CPT inhibited the PI3K/AKT/mTOR signaling pathway, as evidenced by decreased expressions of phospho-PI3K (p-PI3K), p-Akt and p-mTOR. Moreover, CPT significantly suppressed the nuclear expression but increased the cytosolic expression of hypoxia inducible factor-1 alpha (HIF-1 alpha). Collectively, CPT inhibited the growth, invasion, inflammation and angiogenesis in CT26 colon cancer, and at least partly, by regulating the PI3K/Akt/mTOR signaling and the nuclear translocation of HIF-1 alpha.