AC480, formerly BMS-599626, a pan Her inhibitor, enhances radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo.

Investigational New Drugs
Mylin A TorresK Kian Ang

Abstract

The present study investigated the effect of AC480, a small molecule pan-HER tyrosine kinase inhibitor, on in vitro radiosensitivity and in vivo radioresponse of a human head and neck squamous cell carcinoma cell line. HN-5 cells were exposed to γ-radiation with and without AC480 and assayed for proliferation, clonogenic survival, apoptosis, cell cycle distribution, and DNA damage. The cells were analyzed by immunoprecipitation and western blotting for proteins involved in apoptosis, cell cycle regulation, and the EGFR pathway. The effect of AC480 on tumor radioresponse was assessed by tumor growth delay assay using HN5 tumor xenografts generated in nude mice. At the molecular level, in HN-5 cells the agent inhibited the expression of pEGFR, pHER2, cyclins D and E, pRb, pAkt, pMAPK, pCDK1 and 2, CDK 6, and Ku70 proteins. The drug also induced accumulation of cells in the G1 cell cycle phase, inhibited cell growth, enhanced radiosensitivity, and prolonged the presence of γ-H₂AX foci up to 24 h after radiation. AC480 did not increase the percentage of cells undergoing radiation-induced apoptosis. The drug given before and during irradiation improved the radioresponse of HN5 tumors in vivo. AC480 significantly enhanced the radiose...Continue Reading

References

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Citations

Oct 5, 2011·Expert Opinion on Pharmacotherapy·Antarpreet Kaur, Constantin A Dasanu
Sep 25, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Richard L SchroederJayalakshmi Sridhar
Sep 23, 2014·International Journal of Radiation Biology·Yue JinYong Liang
Nov 29, 2011·Cancer Letters·Somaira NowsheenAlexandros G Georgakilas
Mar 13, 2014·Drug Discovery Today·Saurabh PrabhuTimothy J Snape
Feb 13, 2015·Frontiers in Oncology·Xiaochun WangJia-Lin Yang

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