Investigational New Drugs

, Volume 29, Issue 4, pp 554–561

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

  • Mylin A. Torres
  • Uma Raju
  • David Molkentine
  • Oliver Riesterer
  • Luka Milas
  • K. Kian Ang
PRECLINICAL STUDIES

DOI: 10.1007/s10637-010-9389-3

Cite this article as:
Torres, M.A., Raju, U., Molkentine, D. et al. Invest New Drugs (2011) 29: 554. doi:10.1007/s10637-010-9389-3
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Summary

Purpose: 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. Methods: 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. Results: 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. Conclusion: AC480 significantly enhanced the radiosensitivity of HN-5 cells, expressing both EGFR and Her2. The mechanisms involved in the enhancement included cell cycle redistribution and inhibition of DNA repair. Both in vitro and in vivo data from our study suggest that AC480 has potential to increase tumor response to radiotherapy.

Keywords

AC480 Pan-Her inhibitor Radiation Head and neck squamous cell carcinoma cells 

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Mylin A. Torres
    • 1
    • 2
    • 5
  • Uma Raju
    • 3
  • David Molkentine
    • 3
  • Oliver Riesterer
    • 3
    • 4
  • Luka Milas
    • 3
  • K. Kian Ang
    • 2
    • 3
  1. 1.Department of Radiation OncologyWinship Cancer Institute of Emory UniversityAtlantaUSA
  2. 2.Department of Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of Experimental Radiation OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Department of Radiation OncologyUniversity Hospital ZurichZurichSwitzerland
  5. 5.Department of Radiation OncologyEmory University School of MedicineAtlantaUSA

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