Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy

Yanhong Zhang, Jinfa Gu, Lili Zhao, Lingfeng He, Wenbin Qian, Jinhui Wang, Yigang Wang, Qijun Qian, Cheng Qian, Jian Wu, Yuan Liu Xin

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Manganese superoxide dismutase (MnSOD) is a latent tumor suppressor gene. To investigate the therapeutic effect of MnSOD and its mechanisms, a replication-competent recombinant adenovirus with E1B 55-kDa gene deletion (ZD55) was constructed, and human MnSOD and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes were inserted to form ZD55-MnSOD and ZD55-TRAIL. ZD55-MnSOD exhibited an inhibition in tumor cell growth ∼ 1,000-fold greater than Ad-MnSOD. ZD55-TRAIL was shown to induce the MnSOD expression in SW620 cells. Accordingly, by the combined use of ZD55-MnSOD with ZD55-TRAIL (i.e., "dual gene virotherapy"), all established colorectal tumor xenografts were completely eliminated in nude mice. The evidence exists that the MnSOD overexpression led to a slower tumor cell growth both in vitro and in vivo as a result of apoptosis caused by MnSOD and TRAIL overexpression after adenoviral transduction. Our results showed that the production of hydrogen peroxide derived from MnSOD dismutation activated caspase-8, which might down-regulate Bcl-2 expression and induce Bax translocation to mitochondria. Subsequently, Bax translocation enhanced the release of apoptosis-initiating factor and cytochrome c. Cytochrome c finally triggered apoptosis by activating caspase-9 and caspase-3 in apoptotic cascade. Bax-mediated apoptosis seems to be dependent on caspase-8 activation because the inhibition of caspase-8 prevented Bid processing and Bax translocation. In conclusion, our dual gene virotherapy completely eliminated colorectal tumor xenografts via enhanced apoptosis, and this novel strategy points toward a new direction of cancer treatment.

Original languageEnglish (US)
Pages (from-to)4291-4298
Number of pages8
JournalCancer Research
Volume66
Issue number8
DOIs
StatePublished - Apr 15 2006

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Heterografts
Superoxide Dismutase
Colorectal Neoplasms
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Genes
Caspase 8
Cytochromes c
Neoplasms
Caspase 9
Gene Deletion
Therapeutic Uses
Growth
Tumor Suppressor Genes
Adenoviridae
Nude Mice
Caspase 3
Hydrogen Peroxide
Mitochondria

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy. / Zhang, Yanhong; Gu, Jinfa; Zhao, Lili; He, Lingfeng; Qian, Wenbin; Wang, Jinhui; Wang, Yigang; Qian, Qijun; Qian, Cheng; Wu, Jian; Xin, Yuan Liu.

In: Cancer Research, Vol. 66, No. 8, 15.04.2006, p. 4291-4298.

Research output: Contribution to journalArticle

Zhang, Yanhong ; Gu, Jinfa ; Zhao, Lili ; He, Lingfeng ; Qian, Wenbin ; Wang, Jinhui ; Wang, Yigang ; Qian, Qijun ; Qian, Cheng ; Wu, Jian ; Xin, Yuan Liu. / Complete elimination of colorectal tumor xenograft by combined manganese superoxide dismutase with tumor necrosis factor-related apoptosis-inducing ligand gene virotherapy. In: Cancer Research. 2006 ; Vol. 66, No. 8. pp. 4291-4298.
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AU - Gu, Jinfa

AU - Zhao, Lili

AU - He, Lingfeng

AU - Qian, Wenbin

AU - Wang, Jinhui

AU - Wang, Yigang

AU - Qian, Qijun

AU - Qian, Cheng

AU - Wu, Jian

AU - Xin, Yuan Liu

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AB - Manganese superoxide dismutase (MnSOD) is a latent tumor suppressor gene. To investigate the therapeutic effect of MnSOD and its mechanisms, a replication-competent recombinant adenovirus with E1B 55-kDa gene deletion (ZD55) was constructed, and human MnSOD and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes were inserted to form ZD55-MnSOD and ZD55-TRAIL. ZD55-MnSOD exhibited an inhibition in tumor cell growth ∼ 1,000-fold greater than Ad-MnSOD. ZD55-TRAIL was shown to induce the MnSOD expression in SW620 cells. Accordingly, by the combined use of ZD55-MnSOD with ZD55-TRAIL (i.e., "dual gene virotherapy"), all established colorectal tumor xenografts were completely eliminated in nude mice. The evidence exists that the MnSOD overexpression led to a slower tumor cell growth both in vitro and in vivo as a result of apoptosis caused by MnSOD and TRAIL overexpression after adenoviral transduction. Our results showed that the production of hydrogen peroxide derived from MnSOD dismutation activated caspase-8, which might down-regulate Bcl-2 expression and induce Bax translocation to mitochondria. Subsequently, Bax translocation enhanced the release of apoptosis-initiating factor and cytochrome c. Cytochrome c finally triggered apoptosis by activating caspase-9 and caspase-3 in apoptotic cascade. Bax-mediated apoptosis seems to be dependent on caspase-8 activation because the inhibition of caspase-8 prevented Bid processing and Bax translocation. In conclusion, our dual gene virotherapy completely eliminated colorectal tumor xenografts via enhanced apoptosis, and this novel strategy points toward a new direction of cancer treatment.

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