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Induction of reactive oxygen species renders mutant and wild-type K-ras pancreatic carcinoma cells susceptible to Ad.mda-7-induced apoptosis

Oncogene volume 24, pages 585–596 (2005)Cite this article

Abstract

Pancreatic cancer is exceptionally aggressive with no long-term effective therapy. Current interventional approaches, including surgery, radiation and/or chemotherapy, have done little to quell the mortality associated with this malignancy. Subtraction hybridization identified a cancer-specific apoptosis-inducing cytokine gene, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), with a broad range of selective antitumor activity in diverse cancers both in vitro and in vivo in nude mice and recently in patients with advanced carcinomas and melanomas. Unlike most neoplasms, pancreatic cancers display innate resistance to mda-7/IL-24-induced apoptosis, which correlates with a diminished capacity to convert mda-7/IL-24 mRNA into protein. We presently demonstrate that this translational block can be reversed by treatment with agents that elevate reactive oxygen species (ROS). Induction of apoptosis in vitro and suppression of tumorigenesis in vivo in nude mice are induced in pancreatic cancers, irrespective of the status of their K-ras gene, only when tumor cells simultaneously express mda-7/IL-24 and are treated with a ROS-inducer, such as arsenic trioxide (ARS), N-(4-hydroxyphenyl) retinamide (HPR) or dithiophene (NSC656240 (NSC)). In pancreatic cancer cells constitutively expressing mda-7/IL-24 mRNA, a single treatment with arsenic trioxide, HPR or NSC656240 induces apoptosis, which correlates with production of MDA-7/IL-24 protein. The specificity of this action is documented by the ability of ROS inhibitors, including N-acetyl-L-cysteine and Tiron, to block this killing effect. Of potential clinical significance, similar treatment of normal cells does not elicit significant changes in growth nor does it induce apoptosis. Analysis of signal transduction changes in pancreatic carcinoma cells infected with Ad.mda-7 in combination with a ROS-inducer indicate that cell death correlates with modulation of discrete cassettes of multiple signaling pathways in a pancreatic cancer cell-specific manner, supporting global signaling dysregulation as a potential mediator of apoptosis induction. These findings suggest a promising combinatorial approach for safely promoting cell death in pancreatic tumors that provides a rational framework for developing a selective and effective therapy for this invariably fatal cancer.

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Abbreviations

mda-7/IL-24:

melanoma differentiation associated gene-7/interleukin-24

ROS:

reactive oxygen species

ARS:

arsenic trioxide (A2O3)

HPR:

N-(4-hydroxyphenyl) retinamide

NSC:

NCS646240

NAC:

N-acetyl-L-cysteine

pfu:

plaque-forming units

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Acknowledgements

The present studies were supported in part by NIH Grants CA98712 and CA97318, the Lustgarten Foundation for Pancreatic Cancer Research, the Samuel Waxman Cancer Research Foundation and the Chernow Endowment (PBF). PBF is the Michael and Stella Chernow Urological Cancer Research Scientist and a SWCRF Investigator. Support was also provided to PD from DK52825, CA72955, CA88906, DAMD-17-03-233, and a translational research award from the V Foundation. PD is the Universal Professor in Signal Transduction research.

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Authors and Affiliations

  1. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, 10032, USA

    Irina V Lebedeva, Zao-zhong Su, Devanand Sarkar, Rahul V Gopalkrishnan & Paul B Fisher

  2. Department of Medicine, Mount Sinai Medical Center, New York, NY, 10029, USA

    Samuel Waxman

  3. Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Adly Yacoub & Paul Dent

  4. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, 10032, USA

    Paul B Fisher

  5. Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, 10032, USA

    Paul B Fisher

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  1. Irina V Lebedeva
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  2. Zao-zhong Su
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Correspondence to Paul B Fisher.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Lebedeva, I., Su, Zz., Sarkar, D. et al. Induction of reactive oxygen species renders mutant and wild-type K-ras pancreatic carcinoma cells susceptible to Ad.mda-7-induced apoptosis. Oncogene 24, 585–596 (2005). https://doi.org/10.1038/sj.onc.1208183

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