Histone deacetylase inhibitor FK228 enhances adenovirus-mediated p53 family gene therapy in cancer models

Molecular Cancer Therapeutics
Yasushi SasakiTakashi Tokino

Abstract

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 syn...Continue Reading

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Citations

May 5, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Guo-Hua QiuShing Chuan Hooi
Nov 3, 2011·Evidence-based Complementary and Alternative Medicine : ECAM·Wei-Jan HuangChia-Nan Chen
Jul 2, 2009·International Journal of Cancer. Journal International Du Cancer·Vishal KothariRita Mulherkar
Jun 17, 2020·Experimental and Therapeutic Medicine·Huiwu LiLing Liu
May 22, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Masashi IdogawaTakashi Tokino

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