PT  - JOURNAL ARTICLE
AU  - Sasaki, Yasushi
AU  - Negishi, Hideaki
AU  - Idogawa, Masashi
AU  - Suzuki, Hiromu
AU  - Mita, Hiroaki
AU  - Toyota, Minoru
AU  - Shinomura, Yasuhisa
AU  - Imai, Kohzoh
AU  - Tokino, Takashi
TI  - Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models
AID  - 10.1158/1535-7163.MCT-07-0395
DP  - 2008 Apr 01
TA  - Molecular Cancer Therapeutics
PG  - 779--787
VI  - 7
IP  - 4
4099  - http://mct.aacrjournals.org/content/7/4/779.short
4100  - http://mct.aacrjournals.org/content/7/4/779.full
SO  - Mol Cancer Ther2008 Apr 01; 7
AB  - Therapeutic replacement of the wild-type p53 gene has been pursued as a potential gene therapy strategy in a variety of cancer types; however, some cancer models are resistant to p53 in vivo and in vitro. Therefore, to improve p53 gene therapy, it is important to overcome the resistance to p53-mediated apoptosis. Histone deacetylase inhibitors are a novel class of chemotherapeutic agents that are able to reverse the malignant phenotype of transformed cells. A natural histone deacetylase inhibitor, FK228, is reported to enhance adenovirus infection due in part to the up-regulation of coxsackievirus adenovirus receptor expression. In this study, preclinical experiments were done to establish a mechanistic rationale for the combination of adenovirus-mediated p53 family gene transfer and FK228 pretreatment in future clinical trials. Pretreatment with FK228 enhanced apoptosis in human cancer cells through enhanced transduction of Ad-p53. FK228 also induced hyperacetylation of the p53 protein and specifically enhanced p53-mediated Noxa expression. Additionally, the combination of FK228 and Ad-p53 induced Bax translocation to the mitochondria. The double knockdown of Bax and Noxa expression by small interfering RNA antagonized the synergistic effect of Ad-p53 and FK228 on apoptosis induction. In human cancer xenograft models, FK228 significantly increased the therapeutic effectiveness of p53 as well as p63 gene therapy. These results provide a strong rationale for combining p53 gene therapy and FK228 pretreatment in cancer therapy. [Mol Cancer Ther 2008;7(4):779–87]