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Research Articles: Therapeutics, Targets, and Development

Melanoma differentiation associated gene-7/interleukin-24 reverses multidrug resistance in human colorectal cancer cells

Departments of ¹ Urology, ² Neurosurgery, and ³ Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York; ⁴ Departments of Biochemistry and Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia; and ⁵ Division of Gene Therapy, Departments of Medicine, Pathology and Surgery, and the Gene Therapy Center, University of Alabama, Birmingham, Alabama

Requests for reprints: Paul B. Fisher, Departments of Pathology and Urology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. Phone: 212-305-3642; Fax: 212-305-8177. E-mail: pbf1{at}columbia.edu

Abstract

Overexpression of the multidrug resistance 1 (MDR1) gene, encoding P-glycoprotein (P-gp), facilitates resistance to diverse chemotherapeutic drugs and current P-gp inhibitors display high toxicity. We studied the effects of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), which exhibits cancer-specific apoptosis-inducing properties, in drug-sensitive (SW620) and drug-resistant (SW620/Dox) colorectal carcinoma cells. Adenovirus administered mda-7/IL-24, Ad.mda-7, effectively reversed resistance to doxorubicin-induced apoptosis in SW620/Dox cells by increased intracellular accumulation and decreased efflux of doxorubicin. Unexpectedly, P-gp–overexpressing cells (SW620/Dox) displayed increased apoptosis following Ad.mda-7 infection compared with parental SW620 cells, which correlated with more MDA-7/IL-24 protein in SW620/Dox than SW620 cell and potentially explains the increased sensitivity of P-gp–overexpressing cells to mda-7/IL-24. Transient overexpression of MDR1 in SW620 cells significantly increased apoptosis, decreased anchorage-independent growth, and increased MDA-7/IL-24 protein following Ad.mda-7 infection, whereas down-modulation of MDR1 in SW620/Dox cells by small interfering RNA decreased apoptosis following Ad.mda-7 infection. The increased mda-7/IL-24 sensitivity observed in SW620/Dox cells was partly due to increased reactive oxygen species generation and lower mitochondrial membrane potential. These findings confirm that mda-7/IL-24 is a potent MDR reversal agent, preferentially causing apoptosis in P-gp–overexpressing MDR cells, suggesting significant expanded clinical implications for the use of mda-7/IL-24 in treating neoplasms that have failed chemotherapy mediated by the P-gp MDR mechanism. [Mol Cancer Ther 2007;6(11):2985–94]

Grant support: NIH grants R01 CA097318, R01 CA098712, and P01 CA104177; Samuel Waxman Cancer Research Foundation; and Chernow Endowment. P.B. Fisher is the Michael and Stella Chernow Urological Cancer Research Scientist and a Samuel Waxman Cancer Research Foundation Investigator.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ Note: Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 6/13/07; revised 8/31/07; accepted 9/27/07.