Tanshinone IIA derivatives induced S-phase arrest through stabilizing c-myc G-quadruplex DNA to regulate ROS-mediated PI3K/Akt/mTOR pathway

Herein, a derivate from tanshinone IIA, 1,6,6-trimethyl-11-phenyl-7,8,9,10-tetrahydro-6H-furo[2',3':1,2]phe-nanthro[3,4-d]imidazole (TA25), has been synthesized and investigated as potential inhibitor against the pro-liferation, migration and invasion of lung cancer cells. MTT assay and cell colony formation assay results showed that TA25 exhibits acceptable inhibitory effect against the proliferation of lung cancer A549 cells, and the value of IC50 was about 17.9 mu M. This result was further confirmed by the inhibition of TA25 against the growth of xenograft lung cancer cells on zebrafish bearing tumor (A549 lung cancer cells). The results of wound-healing assay and FITC-gelatin invasion assay displayed that TA25 could inhibit the migration and invasion of lung cancer A549 cells. Moreover, the studies on the binding properties of TA25 interact with c-myc G-quadruplex DNA suggested that TA25 can bind in the G-quarter plane formed from G7, G11, G16 and G20 with c-myc G-quadruplex DNA through pi-pi stacking. Further study of the potential anti-cancer mechanism indicated that TA25 can induce S-phase arrest in lung cancer A549 cells, and this phenomenon resulted from the promotion of the production of reactive oxygen species and DNA damage in A549 cells under the action of TA25. Further research revealed that TA25 could inhibit the PI3K/Akt/mTOR signal pathway and increase the expression of p53 protein. Overall, TA25 can be developed into a promising inhibitor against the proliferation, migration and invasion of lung cancer cells and has potential clinical application in the near future.

Automated summary

TA25, a derivate from tanshinone IIA, shows promising inhibitory effects against the proliferation, migration, and invasion of lung cancer cells. Its inhibitory effect was confirmed through MTT assay, cell colony formation assay, xenograft lung cancer cells model, wound-healing assay, FITC-gelatin invasion assay, and binding properties of TA25 interact with c-myc G-quadruplex DNA. TA25 can induce S-phase arrest, increase ROS production, cause DNA damage, inhibit the PI3K/Akt/mTOR signal pathway, and upregulate p53 protein expression in A549 cells.