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Mechanism of In vitro Pancreatic Cancer Cell Growth Inhibition by Melanoma Differentiation–Associated Gene-7/Interleukin-24 and Perillyl Alcohol

Departments of ¹ Urology, ² Pathology, ³ Dermatology, and ⁴ Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York and Departments of ⁵ Human and Molecular Genetics and ⁶ Biochemistry and Molecular Biology, ⁷ VCU Institute of Molecular Medicine, and ⁸ Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia

Requests for reprints: Paul B. Fisher, Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Sanger Hall Building 11-015, 1101 East Marshall Street, Richmond, VA 23298. Phone: 804-828-9632; Fax: 804-827-1124; E-mail: pbfisher{at}vcu.edu.

Key Words: mda-7/IL-24 • POH • reactive oxygen species • cancer-selective apoptosis • xanthine oxidase

The death rate for pancreatic cancer approximates the number of new cases each year, and when diagnosed, current therapeutic regimens provide little benefit in extending patient survival. These dire statistics necessitate the development of enhanced single or combinatorial therapies to decrease the pathogenesis of this invariably fatal disease. Melanoma differentiation–associated gene-7/interleukin-24 (mda-7/IL-24) is a potent cancer gene therapeutic because of its broad-spectrum cancer-specific apoptosis-inducing properties as well as its multipronged indirect antitumor activities. However, pancreatic cancer cells show inherent resistance to mda-7/IL-24 that is caused by a block of translation of mda-7/IL-24 mRNA in these tumor cells. We now reveal that a dietary agent perillyl alcohol (POH) in combination with Ad.mda-7 efficiently reverses the mda-7/IL-24 "protein translational block" by inducing reactive oxygen species, thereby resulting in mda-7/IL-24 protein production, growth suppression, and apoptosis. Pharmacologic inhibitor and small interfering RNA studies identify xanthine oxidase as a major source of superoxide radical production causing these toxic effects. Because both POH and Ad.mda-7 are being evaluated in clinical trials, combining a dietary agent and a virally delivered therapeutic cytokine provides an innovative approach for potentially treating human pancreatic cancer. [Cancer Res 2008;68(18):7439–47]