Preclinical evaluation of the mTOR-PI3K inhibitor BEZ235 in nasopharyngeal cancer models

Brigette B Y Ma; Vivian W Y Lui; Connie W C Hui; Cecilia P Y Lau; Chi H Wong; Edwin P Hui; Margaret H L Ng; Suk H Cheng; Sai W Tsao; Chi-Man Tsang; Crystal S F Cheung; Kakiu Ho; Anthony T C Chan

doi:10.1016/j.canlet.2013.09.007

Preclinical evaluation of the mTOR-PI3K inhibitor BEZ235 in nasopharyngeal cancer models

Cancer Lett. 2014 Feb 1;343(1):24-32. doi: 10.1016/j.canlet.2013.09.007. Epub 2013 Sep 14.

Authors

Affiliations

¹ State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region. Electronic address: brigette@clo.cuhk.edu.hk.
² Department of Otolaryngology, University of Pittsburgh, USA.
³ State Key Laboratory in Oncology in South China, Sir Y.K. Pao Centre for Cancer, Department of Clinical Oncology, Cancer Drug Testing Unit, Hong Kong Cancer Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong Special Administrative Region.
⁴ Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong Special Administrative Region.
⁵ Department of Anatomy, University of Hong Kong, Hong Kong Special Administrative Region.

PMID: 24041865
DOI: 10.1016/j.canlet.2013.09.007

Abstract

The dual PI3K-mTOR inhibitor BEZ235 was evaluated in preclinical models of nasopharyngeal carcinoma (NPC). The IC50 value of BEZ235 for growth was in the nanomolar range in vitro, induce G1 cycle arrest and apoptosis, and inhibited AKT and mTOR signaling in most NPC cell lines. No synergistic effect was observed when BEZ235 was combined with chemotherapy. BEZ235 increased MAPK activation in vitro but not in vivo. A daily schedule was more effective than a weekly schedule on tumor growth and inhibition of downstream mTOR signaling in vivo. The activity of BEZ235 maybe independent of the PIK3CA amplification and mutation status.

Keywords: BEZ235; MAPK activation; Nasopharyngeal carcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Carcinoma
Cell Cycle
Cell Line, Tumor
Cell Survival
Cisplatin / pharmacology
Enzyme Activation
Female
Gene Expression Regulation, Neoplastic*
Humans
Imidazoles / pharmacology*
Inhibitory Concentration 50
MAP Kinase Signaling System
Mice
Mice, Nude
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms / genetics
Nasopharyngeal Neoplasms / metabolism*
Neoplasm Transplantation
Paclitaxel / pharmacology
Phosphatidylinositol 3-Kinases / metabolism*
Phosphoinositide-3 Kinase Inhibitors
Quinolines / pharmacology*
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism*

Substances

Antineoplastic Agents
Imidazoles
Phosphoinositide-3 Kinase Inhibitors
Quinolines
MTOR protein, human
TOR Serine-Threonine Kinases
Paclitaxel
Cisplatin
dactolisib