Lung cancer is one of the most common causes of cancer deaths in the world, and the emergence of resistant lung cancer cells can lead to treatment failure. The development of new drugs to treat lung cancer, especially those resistant lung cancer cells, is urgent. Previously we identified that coumarin could inhibit replication of human lung cancer A549 cells. The efficacy of 284 coumarin derivatives on human lung cancer A549 cells was examined, and BPR2P001S0 was the most potent compound. BPR2P001S0 exhibited growth inhibition and apoptotic activity on A549 cells with an IC50 of 10 nM. A similar level of inhibitory effects was also observed in cisplatin-resistant A549 cells (IC50 = 12.5 nM). The ability of colony formation and migration capability of A549 cells decreased significantly in the presence of BPR2P001S0. In cell cycle analysis, BPR2P001S0 induced cell cycle arrest at the G0/G1 phase through down-regulation of cyclin D1 and Cdk4 protein expression. The expression of cyclinD1/Cdk4 regulatory protein, Akt, was also decreased. Subsequently, we found that the expression level of Ser241 phosphorated PDPK1 protein, an Akt activator in Akt pathway, was also reduced. By molecular docking analysis, we found that the reduced PDPK1 phosphorylation is likely resulted from the allosteric effect of interactions between BPRHIV001 and PDPK1. In conclusion, our results suggest that the anti-tumor activity of BPR2P001S0 is likely resulting from its ability to interfere with PDPK1 autophosphorylation at Ser241, which leads to reduced Akt protein and subsequent cyclin D1 degradation.

Citation Format: Pi-Han Lin, Tzu-Ming Jao, Yu-Lin Hung, Hsing-Pang Hsieh, Ya-Chien Yang, Sui-Yuan Chang. BPR2P001S0, a Coumarin derivative, induced cell cycle arrest in A549 through inhibiting PDPK1 activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1754. doi:10.1158/1538-7445.AM2015-1754

©2015 American Association for Cancer Research.
2015