Cisplatin enhances the antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand gene therapy via recruitment of the mitochondria-dependent death signaling pathway

S. Shamimi-Noori, W. S. Yeow, M. F. Ziauddin, H. Xin, T. L N Tran, J. Xie, A. Loehfelm, P. Patel, J. Yang, D. S. Schrump, B. L. Fang, Dao Nguyen

Research output: Contribution to journalArticle

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Abstract

Despite adequately expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, malignant cells are frequently refractory to the cytotoxic effect of this apoptosis-inducing ligand. The susceptibility of cancer cells to TRAIL can be potentiated by cisplatin (CDDP). This study was designed to evaluate the ability of cisplatin to enhance the cytotoxic effect of TRAIL gene therapy using the recombinant adenovirus-mediated tumor-selective expression of membrane-bound green fluorescence protein (GFP)-TRAIL fusion protein (AdVgTRAIL) on thoracic cancer cells and to elucidate the putative mechanisms responsible for this synergistic combination effect. While causing little death of cultured thoracic cancer cells by itself, AdVgTRAIL in combination with CDDP, on the other hand, mediated profound supra-additive cytotoxicity and apoptosis via a strong bystander effect. CDDP/AdVgTRAIL-induced cytotoxicity was completely abrogated either by the pancaspase inhibitor zVAD-fmk or by the selective caspase 9 inhibitor or by transient knockdown of caspase 9 by siRNA, indicating that this process was caspase-mediated and mitochondria-dependent. This was confirmed by the observation that Bcl2 overexpression protected the cells from combination-induced cytotoxicity. Robust activation of caspase 8 activity in combination-treated cells was blocked by overexpression of Bcl2, indicating that caspase 8 activation was secondary to the mitochondria-mediated amplification feedback loop. Combining CDDP with AdVgTRAIL greatly enhances its tumoricidal efficacy in cultured thoracic cancer cells in vitro. The two agents interact to mediate profound activation of caspase cascade via recruitment of the mitochondria and positive feedback loop. The CDDP/AdVgTRAIL combination also exhibits a strong antitumor effect in in vivo animal model of human cancer xenografts.

Original languageEnglish
Pages (from-to)356-370
Number of pages15
JournalCancer Gene Therapy
Volume15
Issue number6
DOIs
StatePublished - Jun 1 2008

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Genetic Therapy
Cisplatin
Mitochondria
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Neoplasms
Thorax
Caspase 9
Caspase 8
Caspases
TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand Receptors
Bystander Effect
Caspase Inhibitors
Heterografts
Adenoviridae
Small Interfering RNA
Animal Models
Fluorescence

Keywords

  • Adenovirus
  • Esophageal cancer
  • Lung cancer
  • Mesothelioma
  • Mitochondria
  • TRAIL

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Cisplatin enhances the antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand gene therapy via recruitment of the mitochondria-dependent death signaling pathway. / Shamimi-Noori, S.; Yeow, W. S.; Ziauddin, M. F.; Xin, H.; Tran, T. L N; Xie, J.; Loehfelm, A.; Patel, P.; Yang, J.; Schrump, D. S.; Fang, B. L.; Nguyen, Dao.

In: Cancer Gene Therapy, Vol. 15, No. 6, 01.06.2008, p. 356-370.

Research output: Contribution to journalArticle

Shamimi-Noori, S. ; Yeow, W. S. ; Ziauddin, M. F. ; Xin, H. ; Tran, T. L N ; Xie, J. ; Loehfelm, A. ; Patel, P. ; Yang, J. ; Schrump, D. S. ; Fang, B. L. ; Nguyen, Dao. / Cisplatin enhances the antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand gene therapy via recruitment of the mitochondria-dependent death signaling pathway. In: Cancer Gene Therapy. 2008 ; Vol. 15, No. 6. pp. 356-370.
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abstract = "Despite adequately expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors DR4/DR5, malignant cells are frequently refractory to the cytotoxic effect of this apoptosis-inducing ligand. The susceptibility of cancer cells to TRAIL can be potentiated by cisplatin (CDDP). This study was designed to evaluate the ability of cisplatin to enhance the cytotoxic effect of TRAIL gene therapy using the recombinant adenovirus-mediated tumor-selective expression of membrane-bound green fluorescence protein (GFP)-TRAIL fusion protein (AdVgTRAIL) on thoracic cancer cells and to elucidate the putative mechanisms responsible for this synergistic combination effect. While causing little death of cultured thoracic cancer cells by itself, AdVgTRAIL in combination with CDDP, on the other hand, mediated profound supra-additive cytotoxicity and apoptosis via a strong bystander effect. CDDP/AdVgTRAIL-induced cytotoxicity was completely abrogated either by the pancaspase inhibitor zVAD-fmk or by the selective caspase 9 inhibitor or by transient knockdown of caspase 9 by siRNA, indicating that this process was caspase-mediated and mitochondria-dependent. This was confirmed by the observation that Bcl2 overexpression protected the cells from combination-induced cytotoxicity. Robust activation of caspase 8 activity in combination-treated cells was blocked by overexpression of Bcl2, indicating that caspase 8 activation was secondary to the mitochondria-mediated amplification feedback loop. Combining CDDP with AdVgTRAIL greatly enhances its tumoricidal efficacy in cultured thoracic cancer cells in vitro. The two agents interact to mediate profound activation of caspase cascade via recruitment of the mitochondria and positive feedback loop. The CDDP/AdVgTRAIL combination also exhibits a strong antitumor effect in in vivo animal model of human cancer xenografts.",
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AU - Xin, H.

AU - Tran, T. L N

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AU - Loehfelm, A.

AU - Patel, P.

AU - Yang, J.

AU - Schrump, D. S.

AU - Fang, B. L.

AU - Nguyen, Dao

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