Dual Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 Has a Therapeutic Potential and Sensitizes Cisplatin in Nasopharyngeal Carcinoma

Abstract

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.

Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma

“…In this study, GSK2126458 or PKI-587 reduced the levels of phosphorylated Akt, mTOR, S6, and 4EBP1 in a time-and concentration-dependent manner, consistent with other reports in NPC (23,37,38). In addition, we found that very low concentrations of GSK2126458 and PKI-587 could effectively inhibit the migration and invasion of NPC cells, which may be associated with reduced EMT phenotypic expression, indicating the high efficacy of these compounds.…”

“…Recently, we reported that Akt expression in NPC cells and biopsies from patients with NPC could be increased by IR, which is associated with metastasis, suggesting that the PI3K/mTOR pathway might be an ideal therapeutic target in NPC (22). Preclinical studies have demonstrated that targeting the PI3K/mTOR pathway by a dual PI3K/mTOR inhibitor, NVP-BEZ235, sensitized the antitumor effect of cisplatin in NPC (23). However, there is little data about the effect of inhibition of PI3K/Akt/mTOR signaling on tumor progression and radiosensitivity in NPC.…”

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

“…22,23 Furthermore, dual PI3K/mTOR inhibition has also been shown to downregulate Mcl-1 levels in other tumors. [39][40][41][42] It has been proposed that PI3K/mTOR inhibition leads to a downregulation of Mcl-1 due to a block in cap-dependent translation. 23,43 Our studies show that PI3K inhibition using multiple pan-specific and isoform-selective PI3K inhibitors in either AML cell lines or primary AML blasts had very little impact on Mcl-1 levels (Figures 2-3 For personal use only.…”

Effect of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against human Merkel cell carcinoma MKL-1 cells

“…As a PI3K/mTOR inhibitor, NVP-BEZ235 strongly blocks Akt kinase activity, which results in the aforementioned Akt function becoming inefficient, and thereby induces cell cycle arrest in the G1 phase (10). In addition, NVP-BEZ235 has also been associated with the positive regulation of mid-and late-G1 phase cyclin/Cdk activity through the phosphorylation and inactivation of the Cdk inhibitor p21 in MKL-1 cells (29,30). Overall, the decrease in cyclin D1 and increase in p21 and p27 levels may contribute to the G1 cell cycle arrest observed in NVP-BEZ235-treated MKL-1 cells.…”