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Mol Ther Nucleic Acids. 2016 Nov 15;5(11):e384. doi: 10.1038/mtna.2016.90.

Enhanced Anticancer Activity of PF-04691502, a Dual PI3K/mTOR Inhibitor, in Combination With VEGF siRNA Against Non-small-cell Lung Cancer.

Author information

1
Translational Drug Delivery Research (TransDDR) Laboratory, Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, Hawaii, USA.
2
Translational Drug and Gene Delivery Research (TransDGDR) Laboratory, Department of Pharmaceutics and Drug Delivery, School of Pharmacy, University of Mississippi, Oxford, MS.
3
Pii Center for Pharmaceutical Technology, Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS.
4
National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, Oxford, MS.
5
Natural Products and Experimental Therapeutics Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.

Abstract

Lung cancer is the leading cause of cancer deaths in both men and women in the United States accounting for about 27% of all cancer deceases. In our effort to develop newer therapy for lung cancer, we evaluated the combinatory antitumor effect of siRNA targeting VEGF and the PI3K/mTOR dual inhibitor PF-04691502. We analyzed the anticancer effect of siRNA VEGF and PF-04691502 combination on proliferation, colony formation and migration of A549 and H460 lung cancer cells. Additionally, we assessed the combination treatment antiangiogenic effect on human umbilical vein endothelial cells. Here, we show for the first time that the antiangiogenic siRNA VEGF potentiates the PF-04691502 anticancer activity against non-small-cell lung cancer. We observed a significant (P < 0.05) decrease in cell viability, colony formation, and migration for the combination comparing with the single drug treatment. We also showed a significant (P < 0.05) enhanced effect of the combination treatment inhibiting angiogenesis progression and tube formation organization compared to the single drug treatment groups. Our findings demonstrated an enhanced synergistic anticancer effect of siRNA VEGF and PF-04691502 combination therapy by targeting two main pathways involved in lung cancer cell survival and angiogenesis which will be useful for future preclinical studies and potentially for lung cancer patient management.

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