DNA aneuploidy-specific therapy for head and neck squamous cell carcinoma

Head Neck. 2015 Jun;37(6):884-8. doi: 10.1002/hed.23687. Epub 2014 Jun 27.

Abstract

Background: Patients with head and neck squamous cell carcinoma (HNSCC) have an unfavorable prognosis, with a 5-year survival rate of approximately 40%. Genetic analyses have revealed that the majority of HNSCCs carry complex, aneuploid karyotypes, showing numerical and structural chromosomal imbalances. New compounds are being developed that target chromosomal instability in general, specifically affecting cells with aneuploid karyotypes.

Methods: Two such compounds, 5-aminoimidazole-4-carboxamide riboside (AICAR) and 17-allylamino-17-demethoxygeldanamycin (17-AAG), were tested using a panel of stable diploid and unstable aneuploid HNSCC cell lines, and short-term cultures of normal keratinocytes as control.

Results: A significant growth inhibitory effect by both compounds was observed in the aneuploid compared to diploid HNSCC cell lines and to the normal keratinocytes. This effect was independent from the TP53 mutation status. Combination treatment with AICAR and 17-AAG demonstrated the strongest inhibition.

Conclusion: Aneuploidy-targeted therapy may be a viable addition to the treatment options for HNSCC.

Keywords: aneuploidy; cancer therapy; chromosomal instability; head and neck squamous cell carcinoma; tumor cell line.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Aneuploidy*
  • Benzoquinones / pharmacology*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / therapy
  • Case-Control Studies
  • DNA Mutational Analysis
  • Female
  • Genetic Therapy / methods*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / therapy
  • Humans
  • Keratinocytes
  • Lactams, Macrocyclic / pharmacology*
  • Male
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Mutation, Missense
  • Ribonucleosides / pharmacology*
  • Sensitivity and Specificity
  • Squamous Cell Carcinoma of Head and Neck
  • Treatment Outcome
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Benzoquinones
  • Lactams, Macrocyclic
  • Ribonucleosides
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Aminoimidazole Carboxamide
  • tanespimycin
  • acadesine