Novel Phosphoinositide 3-Kinase/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibitory Activity against Human Head and Neck Cancer Cells In Vitro and In Vivo

Abstract

Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently accounts for the tumorigenesis in head and neck cancer. To develop a new treatment, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in head and neck cancer cells.Experimental Design: The in vitro antitumor effect of BGT226 was determined in various cancer cell lines. Animal models were also applied to examine drug potency. The inhibitory ability of BGT226 on the PI3K/AKT/mTOR signaling pathway was analyzed.Results: The growth inhibition assay revealed that BGT226 was active against all tested cancer cell lines. Cross-resistance was not observed in the cisplatin-resistant cell line. The activation of the AKT/mTOR signal cascade was suppressed by BGT226 in a concentration-and time-dependent manner. Flow cytometric analysis revealed an accumulation of cells in the G 0 -G 1 phase with concomitant loss in the S-phase. Results of the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and the analysis of caspase 3/7 and PARP indicated that BGT226 induced cancer cell death through an apoptosisindependent pathway. BGT226 induced autophagy as indicated by the aggregation and upregulation of the microtubule-associated protein light chain 3B-II, and p62 degradation. Gene silencing of Beclin1 or cotreatment of the autophagosome inhibitor, 3-methyladenine, inhibited the BGT226-induced autophagy and led to the retrieval of colony survival. In a xenografted animal model, BGT226 significantly delayed tumor growth in a dose-dependent manner, along with suppressed cytoplasmic expression of p-p70 S6 kinase and the presence of autophagosome formation.Conclusions: These data indicate that BGT226 is a potential drug in the treatment of head and neck cancer. Clin Cancer Res; 17(22); 7116-26. Ó2011 AACR.

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

“…These data are of interest in light of a previous study where knockdown of p130Cas, which signals downstream of FAK, resulted in enhanced autophagy in ovarian cancer cells (43) and add further weight to the emerging concept that the role of autophagy in cancer development and progression is highly context dependent. Thus, while specific autophagy genes, such as Beclin-1, can act as tumor suppressors (44), and particular drug regimens can exert cytotoxicity through autophagic cell death (45,46) induction of autophagy can also confer drug resistance to cancer cells, for example, against the TKIs erlotinib (47) and saracatinib (48). Moreover, our work also emphasizes how FAK signaling can exert contrasting effects on autophagy and cell survival.…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…It has shown efficacy in inhibiting estrogen-deprived ER positive breast cancer cell lines, multiple myelomas and head and neck cancers [95][96][97] . The modes of inhibition by BGT226 vary in different types of cancer cell lines.…”

“…But, on the contrary, BGT226 inhibits head and neck cancer in an apoptosis-independent manner. Instead of apoptosis, BGT226 induces autophagy, which is regulated by upregulation of the microtubule-associated protein light chain 3B-II and p62 degradation [97] . XL-147 (structure not disclosed) is a low-molecular-weight, potent, orally bioavailable PI3K inhibitor that recently went into phase II clinical trials for advanced or recurrent endometrial cancer (www.clinicaltrials.gov).…”

Análise da expressão e mecanismos de ação das proteínas Akt, Hsp90, mTOR e ciclina D1 em cultura de células de carcinoma epidermoide humano e células displásicas após irradiação com laser em baixa intensidade

“…O mesmo estudo aponta para uma análise imuno-histoquímica condizente, em que a expressão citoplasmática de p-p70S6K foi atenuada após o tratamento in vitro (132) .…”

“…Da mesma maneira, quimioterápicos devem, em geral, reduzir a expressão de ciclina D1 no câncer, uma vez que esta é um dos marcadores importantes para o prognóstico de tumores (162,163) . Chang et al, por exemplo, mostraram que a droga BGT226 bloqueia ambos Akt e mTOR, levando à expressão atenuada de suas proteínas downstream, como p-GSK-3β, p-p70S6K e p-4E-BP1, o que resulta em supressão da expressão de ciclina D1 nas células de CECP (132) .…”