A combination treatment with SAHA and ad-p63/p73 shows an enhanced anticancer effect in HNSCC.
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.
Shim
Seon-Hui
SH
Department of Molecular Tumor Biology, College of Medicine, Seoul National University, Seoul, South Korea.
Lee
Choon-Taek
CT
Lee
Jae-Jung
JJ
Kim
So-Yeon
SY
Hah
J Hun
JH
Heo
Dae Seog
DS
Sung
Myung-Whun
MW
D000256:Adenoviridae / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D016896:Treatment Outcome; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D000077337:Vorinostat
D000970:Antineoplastic Agents; C081876:CKAP4 protein, human; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011991:Receptors, Virus; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000077337:Vorinostat; D008156:Luciferases; D011065:Poly(ADP-ribose) Polymerases