Combination of Radiotherapy and Adenovirus-Mediated p53 Gene Therapy for MDM2-Overexpressing Hepatocellular Carcinoma
- Authors
- Koom, WS; Park, SY; Kim, W; Kim, M; Kim, JS; Kim, H; Choi, IK; Yun, CO; Seong, J
- Issue Date
- Mar-2012
- Publisher
- OXFORD UNIV PRESS
- Keywords
- p53; MDM2; Radiotherapy; Adenovirus; Gene therapy
- Citation
- JOURNAL OF RADIATION RESEARCH, v.53, no.2, pp.202 - 210
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF RADIATION RESEARCH
- Volume
- 53
- Number
- 2
- Start Page
- 202
- End Page
- 210
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/27569
- DOI
- 10.1269/jrr.11110
- ISSN
- 0449-3060
- 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-Hep1) 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-Hep1 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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