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7095201 
Journal Article 
A novel dual PI3K alpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells 
Zou, ZuQ; Zhang, XH; Wang, F; Shen, QiJun; Xu, Jin; Zhang, LiNa; Xing, WenHua; Zhuo, RenJie; Li, Duo; , 
2009 
Yes 
International Journal of Molecular Medicine
ISSN: 1107-3756
EISSN: 1791-244X 
SPANDIDOS PUBL LTD 
ATHENS 
97-101 
19513541 
WOS:000267230900015 
PI-103, the first synthetic multitargeted compound which simultaneously inhibits PI31K alpha and mammalian target of rapamycin (mTOR) shows high antitumor activity in glioma xenografts. In the present study, clear antitumor activity was observed with PI-103 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460, by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition. In addition, H460 cells with activating mutations of PIK3CA were more sensitive to PI-103 than A549 cells with wild-type PIK3CA. PI-103 was found to inhibit growth by causing GO-G, arrest in A549 and H460 cells. Western blotting showed that PI-103 induced down-regulation of cyclin D1 and E1 and simultaneously up-regulated p21 and p27, associated with arrest in the G(0)-G(1) phase of the cell cycle. Furthermore, p53, the tumor suppressor which transcriptionally regulates p21, was also upregulated with PI-103 treatment. Collectively, our results suggest that multitargeted intervention is the most effective tumor therapy, and the cooperative blockade of PI3K alpha and mTOR with PI-103 shows promise for treating gefitinib-resistant NSCLC.