The combination of RAD001 and NVP-BEZ235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo.

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.

• Authors: Cheng-Xiong Xu, Yikun Li, Ping Yue, Taofeek K Owonikoko, Suresh S Ramalingam, Fadlo R Khuri, Shi-Yong Sun
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e20899 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21695126 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Eukaryotic Initiation Factor-4F
• Imidazoles
• Proto-Oncogene Proteins c-myc
• Quinolines
• Cyclin D1
• Everolimus
• TOR Serine-Threonine Kinases
• dactolisib
• Sirolimus

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin D1 (metabolism)
• Down-Regulation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Eukaryotic Initiation Factor-4F (metabolism)
• Everolimus
• Female
• G1 Phase (drug effects)
• Humans
• Imidazoles (pharmacology)
• Lung Neoplasms (pathology)
• Mice
• Proto-Oncogene Proteins c-myc (metabolism)
• Quinolines (pharmacology)
• Signal Transduction (drug effects)
• Sirolimus (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays