Abstract 4471: Novel PI3K/mTOR dual inhibitor, NVP-BGT226, displays potent inhibitory activity against human head and neck cancer cell growth in vitro and in vivo

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Dysregulation of PI3K/AKT/mTOR signaling pathway is frequently observed in head and neck cancer, and often accounts for its tumorigenesis. To develop new treatment strategy in human head and neck cancer, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226, in head and neck cancer cell lines and one nasopharygeal cancer cell line (HONE-1) with its cisplatin-resistant variants. The growth inhibition assay revealed that NVP-BGT226 was active against all tested tumor cell lines with IC50 values ranged from 7.4 to 27.8 nM. In addition, cross-resistance of this compound to cisplatin-resistant cell lines was not observed. The expression level of p-AKT (S473), p-mTOR (S2481) was decreased in a dose- and time-dependent manner, with a concurrent downregulation in the level of p-4E-BP1 and p-S6P70K. Cell cycle analysis revealed that cells treated with NVP-BGT226 resulted in a dose- and time-dependent accumulation in the Go/G1 phase with concomitant loss in the S phase. The observation in annexin V assay showed an increment of double-staining cells in a time-dependent manner. Interestingly, the cleavage of caspase 3 and PARP was not noted. Further autophagy studies showed that NVP-BGT226 induced autophagy by the conversion of LC3-II from LC3-I. In addition, the accumulation of autophagosome by acridine orange staining was detected. Moreover, the treatment of cells by 3MA 1.25μM blocked the autophasome formation. Collectively, these data indicated that the growth inhibition effect induced by NVP-BGT226 was manipulated through the induction of autophagy. Notably, oral feeding of NVP-BGT226 5 mg/kg daily for 21 days showed potent activity against tumor growth in FaDu xenograft model. In conclusion, our studies suggested that NVP-BGT226 is a potent anti-cancer compound in head and neck cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4471.