PARP1 is overexpressed in nasopharyngeal carcinoma and its inhibition enhances radiotherapy

Mol Cancer Ther. 2013 Nov;12(11):2517-28. doi: 10.1158/1535-7163.MCT-13-0010. Epub 2013 Aug 26.


Nasopharyngeal carcinoma is a rare but highly invasive cancer. As options of agents for effective combination chemoradiotherapy for advanced nasopharyngeal carcinoma are limited, novel therapeutic approaches are desperately needed. The ubiquitin ligase CHFR is known to target PARP1 for degradation and is epigenetically inactivated in nasopharyngeal carcinoma. We present evidence that PARP1 protein is indeed overexpressed in nasopharyngeal carcinoma cells in comparison with immortalized normal nasopharyngeal epithelial cells. Tissue microarray analysis also indicated that PARP1 protein is significantly elevated in primary nasopharyngeal carcinoma tissues, with strong correlation with all stages of nasopharyngeal carcinoma development. We found that the PARP inhibitor AZD2281 (olaparib) increased DNA damage, cell-cycle arrest, and apoptosis in nasopharyngeal carcinoma cells challenged with ionizing radiation or temozolomide. Isobologram analysis confirmed that the cytotoxicity triggered by AZD2281 and DNA-damaging agents was synergistic. Finally, AZD2281 also enhanced the tumor-inhibitory effects of ionizing radiation in animal xenograft models. These observations implicate that PARP1 overexpression is an early event in nasopharyngeal carcinoma development and provide a molecular basis of using PARP inhibitors to potentiate treatment of nasopharyngeal carcinoma with radio- and chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Carcinoma
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Combined Modality Therapy
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / genetics
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / radiotherapy
  • Nasopharyngeal Neoplasms / therapy*
  • Neoplasms, Experimental
  • Phthalazines / administration & dosage*
  • Phthalazines / pharmacology
  • Piperazines / administration & dosage*
  • Piperazines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / genetics*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Temozolomide
  • Tissue Array Analysis
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Dacarbazine
  • Poly(ADP-ribose) Polymerases
  • olaparib
  • Temozolomide