Mechanism of in vitro pancreatic cancer cell growth inhibition by melanoma differentiation-associated gene-7/interleukin-24 and perillyl alcohol.

Abstract

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.

• Authors: Irina V Lebedeva, Zhao-zhong Su, Nichollaq Vozhilla, Lejuan Chatman, Devanand Sarkar, Paul Dent, Mohammad Athar, Paul B Fisher
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 18 Pg. 7439-47 (Sep 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18768668 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Interleukins
• Monoterpenes
• RNA, Messenger
• RNA, Small Interfering
• Reactive Oxygen Species
• interleukin-24
• perillyl alcohol
• Xanthine Oxidase

Topics

• Adenoviridae (genetics)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Cell Growth Processes (drug effects, physiology)
• Cell Line, Tumor
• Combined Modality Therapy
• Down-Regulation
• Genetic Therapy
• Genetic Vectors (genetics)
• Humans
• Interleukins (biosynthesis, genetics)
• Monoterpenes (pharmacology)
• Pancreatic Neoplasms (genetics, metabolism, pathology, therapy)
• Polyribosomes (genetics, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Xanthine Oxidase (biosynthesis, genetics, metabolism)