Augmentation of antitumor effects of p53 gene therapy by combination with HDAC inhibitor.
We have previously shown that the HDAC inhibitors (HDACI) activate the p53 molecule through acetylation of 320 and 373 lysine residues, upregulate PIG3 and NOXA and induce apoptosis in cancer cells expressing wild and pseudo-wild type p53 genes (Terui T, et al. Cancer Res 2003; 63:8948-54). It has also been reported that expression of the Coxsackie adenovirus receptor and subsequent transfection efficiency of the adenovirus in cancer cells were enhanced by HDACI treatment. In this study, we extended these observations to explore the combination effect of adenoviral vector carrying wild type p53 (Ad-p53) gene therapy with a HDACI, sodium butyrate (SB), on xenografted human gastric cancer cells (KATO-III) and hepatocellular carcinoma cells (HuH7) in nude mice. We first confirmed an increased expression of Coxsackie adenovirus receptors with an associated increment of transgene (X-gal) expression by SB treatment in KATO-III cells. We then injected Ad-p53 into subcutaneous tumors of KATO-III and HuH7 combined with intraperitoneal administration of SB and found a significantly higher growth suppressive effect than single treatments of each. Even a complete regression of tumors was observed in three of five mice treated with this combination while with single treatment no tumor regression was observed. Tumors treated with the combination showed higher numbers of TUNEL positive cells than those treated with a single modality. Moreover, necrotic changes were more evident in tumors treated with the combination than separately, a compatible finding to the observation that vascularity revealed by CD34 staining was poorer in tumors treated with the combination than those treated with p53 gene or SB alone. This was further supported by the finding that BAI-1 (brain specific angiogenesis inhibitor-1), an inhibitor of vascularization, was induced by SB treatment in KATO-III and HuH7 cells transfected with Ad-p53. Thus SB was shown to be an efficient potentiator of p53 gene therapy for cancer.
Takimoto
Rishu
R
Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Kato
Junji
J
Terui
Takeshi
T
Takada
Koichi
K
Kuroiwa
Ganji
G
Wu
Jing
J
Ohnuma
Hiroyuki
H
Takahari
Daisuke
D
Kobune
Masayoshi
M
Sato
Yasushi
Y
Takayama
Tetsuji
T
Matsunaga
Takuya
T
Niitsu
Yoshiro
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016158:Genes, p53; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000473:pathology / Q000628:therapy; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000627:therapeutic use*
D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D016159:Tumor Suppressor Protein p53