Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2-overexpressing hepatocellular carcinoma

Woong Sub Koom, Soo Yeon Park, Wonwoo Kim, Minjung Kim, Ji Seong Kim, Hyunki Kim, Il Kyu Choi, Chae Ok Yun, Jinsil Seong

Research output: Contribution to journalArticle

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Abstract

The p53 gene plays a determinant role in radiation-induced cell death and its protein product is negatively regulated by MDM2. We investigated whether adenovirus-mediated modified p53 gene transfer, which blocks p53-MDM2 binding, is effective for radiation-induced cell death in hepatocellular carcinoma (HCC) at different MDM2 cellular levels. Human hepatocellular carcinoma cell lines expressing MDM2 at low levels (Huh7) and high levels (SK-Hepl) were used. Ad-p53 and Ad-p53vp are replication-deficient adenoviral vectors containing human wild-type or modified p53, respectively. The anti-tumor effect was highest for Ad-p53 + radiotherapy (RT) in the low-level MDM2 cells, whereas this effect was highest for Ad-p53vp + RT in the MDM2-overexpressing cells. In Huh-7 cells, Ad-p53 + RT decreased cell viability (32%) in vitro and inhibited tumor growth (enhancement factor, 1.86) in vivo. Additionally, p21 expression and apoptosis were increased. In contrast, in SK-Hepl cells, Ad-p53vp + RT showed decreased cell viability (51%) in vitro and inhibition of tumor growth (enhancement factor, 3.07) in vivo. Caspase-3 expression and apoptosis were also increased. Adenovirus-expressing modified p53, which blocks p53- MDM2 binding, was effective in killing tumor cells overexpressing MDM2. Furthermore, the combination strategy for disruption of the p53-MDM2 interaction with RT demonstrated enhanced anti-tumor effects both in vitro and in vivo.

Original languageEnglish
Pages (from-to)202-210
Number of pages9
JournalJournal of Radiation Research
Volume53
Issue number2
DOIs
Publication statusPublished - 2012 Mar 1

Fingerprint

adenoviruses
gene therapy
p53 Genes
Adenoviridae
Genetic Therapy
Hepatocellular Carcinoma
radiation therapy
Radiotherapy
tumors
cancer
apoptosis
Neoplasms
cells
viability
death
genes
Cell Survival
Intercellular Signaling Peptides and Proteins
Cell Death
Radiation

All Science Journal Classification (ASJC) codes

  • Radiation
  • Radiology Nuclear Medicine and imaging
  • Health, Toxicology and Mutagenesis

Cite this

Koom, Woong Sub ; Park, Soo Yeon ; Kim, Wonwoo ; Kim, Minjung ; Kim, Ji Seong ; Kim, Hyunki ; Choi, Il Kyu ; Yun, Chae Ok ; Seong, Jinsil. / Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2-overexpressing hepatocellular carcinoma. In: Journal of Radiation Research. 2012 ; Vol. 53, No. 2. pp. 202-210.
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Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2-overexpressing hepatocellular carcinoma. / Koom, Woong Sub; Park, Soo Yeon; Kim, Wonwoo; Kim, Minjung; Kim, Ji Seong; Kim, Hyunki; Choi, Il Kyu; Yun, Chae Ok; Seong, Jinsil.

In: Journal of Radiation Research, Vol. 53, No. 2, 01.03.2012, p. 202-210.

Research output: Contribution to journalArticle

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T1 - Combination of radiotherapy and adenovirus-mediated p53 gene therapy for MDM2-overexpressing hepatocellular carcinoma

AU - Koom, Woong Sub

AU - Park, Soo Yeon

AU - Kim, Wonwoo

AU - Kim, Minjung

AU - Kim, Ji Seong

AU - Kim, Hyunki

AU - Choi, Il Kyu

AU - Yun, Chae Ok

AU - Seong, Jinsil

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N2 - The p53 gene plays a determinant role in radiation-induced cell death and its protein product is negatively regulated by MDM2. We investigated whether adenovirus-mediated modified p53 gene transfer, which blocks p53-MDM2 binding, is effective for radiation-induced cell death in hepatocellular carcinoma (HCC) at different MDM2 cellular levels. Human hepatocellular carcinoma cell lines expressing MDM2 at low levels (Huh7) and high levels (SK-Hepl) were used. Ad-p53 and Ad-p53vp are replication-deficient adenoviral vectors containing human wild-type or modified p53, respectively. The anti-tumor effect was highest for Ad-p53 + radiotherapy (RT) in the low-level MDM2 cells, whereas this effect was highest for Ad-p53vp + RT in the MDM2-overexpressing cells. In Huh-7 cells, Ad-p53 + RT decreased cell viability (32%) in vitro and inhibited tumor growth (enhancement factor, 1.86) in vivo. Additionally, p21 expression and apoptosis were increased. In contrast, in SK-Hepl cells, Ad-p53vp + RT showed decreased cell viability (51%) in vitro and inhibition of tumor growth (enhancement factor, 3.07) in vivo. Caspase-3 expression and apoptosis were also increased. Adenovirus-expressing modified p53, which blocks p53- MDM2 binding, was effective in killing tumor cells overexpressing MDM2. Furthermore, the combination strategy for disruption of the p53-MDM2 interaction with RT demonstrated enhanced anti-tumor effects both in vitro and in vivo.

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