the combination of rad001 and nvp-bez235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivorad001和nvp-bez235发挥协同抗癌活性与非小细胞肺癌在体外和体内.pdfVIP

The Combination of RAD001 and NVP-BEZ235 Exerts Synergistic Anticancer Activity against Non-Small Cell Lung Cancer In Vitro and In Vivo Cheng-Xiong Xu, Yikun Li, Ping Yue, Taofeek K. Owonikoko, Suresh S. Ramalingam, Fadlo R. Khuri, Shi- Yong Sun* Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia, United States of America Abstract The phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling axis has emerged as a novel target for cancer therapy. Agents that inhibit PI3K, mTOR or both are currently under development. The mTOR allosteric inhibitor, RAD001, and the PI3K/mTOR dual kinase inhibitor, BEZ235, are examples of these agents. We were interested in developing strategies to enhance mTOR-targeted caner therapy. In this study, we found that BEZ235 alone effectively inhibited the growth of rapamycin-resistant cancer cells. Interestingly, the combination of sub-optimal concentrations of RAD001 and BEZ235 exerted synergistic inhibition of the growth of human lung cancer cells along with induction of apoptosis and G1 arrest. Furthermore, the combination was also more effective than either agent alone in inhibiting the growth of lung cancer xenografts in mice. The combination showed enhanced effects on inhibiting mTOR signaling and reducing the expression of c-Myc and cyclin D1. Taken together, our results suggest that the combination of RAD001 and BEZ235 is a novel strategy for cancer therapy. Citation: Xu C-X, Li Y, Yue P, Owonikoko TK, Ramalingam SS, et al. (2011) The Combination of RAD001 and NVP-BEZ235 Exerts Synergistic Anticancer Activity against Non-Small Cell Lung Cancer In Vitro and In Vivo. PLoS ONE 6(6): e20899. doi:10.1371/journal.pone.0020899 Editor: Gen Sheng Wu, Wayne State University, United States of America Receive