Tumor Biology

, Volume 31, Issue 6, pp 659–666 | Cite as

A combination treatment with SAHA and ad-p63/p73 shows an enhanced anticancer effect in HNSCC

  • Seon-Hui Shim
  • Choon-Taek Lee
  • Jae-Jung Lee
  • So-Yeon Kim
  • J. Hun Hah
  • Dae Seog Heo
  • Myung-Whun Sung
Research Article


Suberoylanilide hydroxamic acid (SAHA) is one of the most widely used histone deacetylase inhibitors. However, the potential advantage of SAHA has not been sufficiently validated as an adjunct to gene therapy of head and neck squamous cell carcinoma (HNSCC). SAHA has been shown to boost the efficiency of gene transfer by upregulating the expression of coxsackie adenoviral receptor on treated cells. The p53 family genes, p63 and p73, have been shown to have characteristics similar to p53, and although they are not confirmed as tumor suppressors, DNA-damaging signals induce their overexpression. We previously reported that the adenovirus-mediated transfer of p63 or p73 showed an effective cancer-killing effect similar to that of p53. In this study, we combined SAHA with adenoviral delivery of p63 or p73 to enhance the efficiency of gene therapy. This combination resulted in a significantly enhanced cancer-killing effect in HNSCC cell lines but had no effect on normal human fibroblasts. SAHA treatment added to ad-p63/p73 gene delivery caused an increase in p21 expression and cleaved poly-ADP ribose polymerase. Our results indicate that adjuvant SAHA treatment could be developed as a therapeutic strategy to enhance the efficiency of adenoviral gene transfer in the treatment of cancer.


Combination gene therapy p63 p73 SAHA HNSCC 



This study was supported by Korea Science and Engineering Foundation grants 2005-01159(M-W Sung), 2008-00728(C-T Lee), and 314-2007-1-E00114 (M-W Sung).

Disclosure Statement

The authors declare that they have no conflict of interest.


  1. 1.
    Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer. 2001;1:194–202.CrossRefPubMedGoogle Scholar
  2. 2.
    Dokmanovic M, Marks PA. Prospects: histone deacetylase inhibitors. J Cell Biochem. 2005;96:293–304.CrossRefPubMedGoogle Scholar
  3. 3.
    Sakuma T, Uzawa K, Onda T, Shiiba M, Yokoe H, Shibahara T, et al. Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. Int J Oncol. 2006;29:117–24.PubMedGoogle Scholar
  4. 4.
    Bhalla KN. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. J Clin Oncol. 2005;23:3971–93.CrossRefPubMedGoogle Scholar
  5. 5.
    Kelly WK, O’Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005;23:3923–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Blumenschein Jr GR, Kies MS, Papadimitrakopoulou VA, Lu C, Kumar AJ, Ricker JL, et al. Phase II trial of the histone deacetylase inhibitor vorinostat (Zolinza, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs. 2008;26:81–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin Jr WG, Levrero M, et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature. 1999;399:806–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Dohn M, Zhang S, Chen X. p63alpha and DeltaNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes. Oncogene. 2001;20:3193–205.CrossRefPubMedGoogle Scholar
  9. 9.
    Shimada A, Kato S, Enjo K, Osada M, Ikawa Y, Kohno K, et al. The transcriptional activities of p53 and its homologue p51/p63: similarities and differences. Cancer Res. 1999;59:2781–6.PubMedGoogle Scholar
  10. 10.
    Flores ER, Sengupta S, Miller JB, Newman JJ, Bronson R, Crowley D, et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell. 2005;7:363–73.CrossRefPubMedGoogle Scholar
  11. 11.
    DeYoung MP, Johannessen CM, Leong CO, Faquin W, Rocco JW, Ellisen LW. Tumor-specific p73 up-regulation mediates p63 dependence in squamous cell carcinoma. Cancer Res. 2006;66:9362–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW. p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell. 2006;9:45–56.CrossRefPubMedGoogle Scholar
  13. 13.
    Jee YS, Lee SG, Lee JC, Kim MJ, Lee JJ, Kim DY, et al. Reduced expression of coxsackie virus and adenovirus receptor (CAR) in tumor tissue compared to normal epithelium in head and neck squamous cell carcinoma patients. Anticancer Res. 2002;22:2629–34.PubMedGoogle Scholar
  14. 14.
    Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science. 1997;275:1320–3.CrossRefPubMedGoogle Scholar
  15. 15.
    Lee JJ, Kim S, Yeom YI, Heo DS. Enhanced specificity of the p53 family proteins-based adenoviral gene therapy in uterine cervical cancer cells with E2F1-responsive promoters. Cancer Biol Ther. 2006;5:1502–10.CrossRefPubMedGoogle Scholar
  16. 16.
    Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, et al. Isolation of a common receptor for coxsackie B viruses and adenoviruses 2 and 5. Science. 1997;275:1320–3.CrossRefPubMedGoogle Scholar
  17. 17.
    Pong RC, Lai YJ, Chen H, Okegawa T, Frenkel E, Sagalowsky A, et al. Epigenetic regulation of coxsackie and adenovirus receptor (CAR) gene promoter in urogenital cancer cells. Cancer Res. 2003;63:8680–6.PubMedGoogle Scholar
  18. 18.
    Wang TY, Chen BF, Yang YC, Chen H, Wang Y, Cviko A, et al. Histologic and immunophenotypic classification of cervical carcinomas by expression of the p53 homologue p63: a study of 250 cases. Hum Pathol. 2001;32:479–86.CrossRefPubMedGoogle Scholar
  19. 19.
    Hu H, Xia SH, Li AD, Xu X, Cai Y, Han YL, et al. Elevated expression of p63 protein in human esophageal squamous cell carcinomas. Int J Cancer. 2002;102:580–3.CrossRefPubMedGoogle Scholar
  20. 20.
    Weber A, Bellmann U, Bootz F, Wittekind C, Tannapfel A. Expression of p53 and its homologues in primary and recurrent squamous cell carcinomas of the head and neck. Int J Cancer. 2002;99:22–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Massion PP, Taflan PM, Jamshedur Rahman SM, Yildiz P, Shyr Y, Edgerton ME, et al. Significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res. 2003;63:7113–21.PubMedGoogle Scholar
  22. 22.
    Sniezek JC, Matheny KE, Westfall MD, Pietenpol JA. Dominant negative p63 isoform expression in head and neck squamous cell carcinoma. Laryngoscope. 2004;114:2063–72.CrossRefPubMedGoogle Scholar
  23. 23.
    Deyoung MP, Ellisen LW. p63 and p73 in human cancer: defining the network. Oncogene. 2007;26:5169–83.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2010

Authors and Affiliations

  • Seon-Hui Shim
    • 1
    • 2
  • Choon-Taek Lee
    • 4
    • 5
  • Jae-Jung Lee
    • 1
    • 2
  • So-Yeon Kim
    • 1
    • 2
  • J. Hun Hah
    • 3
  • Dae Seog Heo
    • 1
    • 2
    • 6
    • 7
  • Myung-Whun Sung
    • 1
    • 2
    • 3
    • 7
    • 8
  1. 1.Department of Molecular Tumor BiologyCollege of Medicine, Seoul National UniversitySeoulSouth Korea
  2. 2.Cancer Research InstituteSeoul National University College of MedicineSeoulSouth Korea
  3. 3.Department of OtorhinolaryngologySeoul National University College of MedicineSeoulSouth Korea
  4. 4.Division of Pulmonary and Care Medicine, Department of Internal MedicineLung Institute of Medical Research CenterSeongnamSouth Korea
  5. 5.Department of Medicine and Respiratory CenterSeoul National University Bundang HospitalSeongnamSouth Korea
  6. 6.Department of Internal MedicineSeoul National University HospitalSeoulSouth Korea
  7. 7.Sensory Organ Research InstituteSeoul National University Medical Research CenterSeoulSouth Korea
  8. 8.Clinical Research InstituteSeoul National University HospitalSeoulSouth Korea

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