Phosphoinositide 3-kinase (PI3K)/AKT/
mammalian target of rapamycin inhibitor (mTOR) pathway is often constitutively activated in human
tumor cells and thus has been considered as a promising
drug target. To ascertain a therapeutical approach of
nasopharyngeal carcinoma (NPC), we hypothesized
NVP-BEZ235, a novel and potent imidazo[4,5-c]
quinolone derivative, that dually inhibits both PI3K and mTOR
kinases activities, had antitumor activity in NPC. Expectedly, we found that
NVP-BEZ235 selectively inhibited proliferation of NPC cells rather than normal nasopharyngeal cells using MTT assay. In NPC cell lines, with the extended exposure,
NVP-BEZ235 selectively inhibited proliferation of NPC cells harboring PIK3CA mutation, compared to cells with wild-type PIK3CA. Furthermore, exposure of NPC cells to
NVP-BEZ235 resulted in G1 growth arrest by
Propidium iodide uptake assay, reduction of
cyclin D1and CDK4, and increased levels of P27 and P21 by Western blotting, but negligible apoptosis. Moreover, we found that
cisplatin (CDDP) activated PI3K/AKT and
mTORC1 pathways and
NVP-BEZ235 alleviated the activation by CDDP through dually targeting PI3K and mTOR
kinases. Also,
NVP-BEZ235 combining with CDDP synergistically inhibited proliferation and induced apoptosis in NPC cells. In CNE2 and HONE1 nude mice xenograft models, orally
NVP-BEZ235 efficiently attenuated
tumor growth with no obvious toxicity. In combination with
NVP-BEZ235 and CDDP, there was dramatic synergy in shrinking
tumor volumes and inducing apoptosis through increasing Noxa, Bax and decreasing Mcl-1, Bcl-2. Based on the above results,
NVP-BEZ235, which has entered phase I/II clinical trials in patients with advanced solid
tumors, has a potential as a monotherapy or in combination with CDDP for NPC treatment.