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Forum on Immunopathological Diseases and Therapeutics
SJR: 0.309 SNIP: 0.041 CiteScore™: 0.18

ISSN Druckformat: 2151-8017
ISSN Online: 2151-8025

Archives: Volume 1, 2010 to Volume 7, 2016

Forum on Immunopathological Diseases and Therapeutics

DOI: 10.1615/ForumImmunDisTher.v1.i4.30
pages 281-295

DETANONOate Is a Potent Chemo\ Radio-Sensitizing Agent in Colon and Colorectal Cancers as Assessed in In Vitro and In Vivo Established Tumor Xenografts

Sergio Huerta
Division of Surgery, University of Texas Southwestern Medical Center, Dallas VA Medical Center, 4500 S. Lancaster Road, Dallas, TX 75225
Xiaohuan Gao
Department of Surgery University of Texas Southwestern Medical Center/Dallas and VA Medical Center, Dallas, TX
Benjamin Bonavida
Department of Microbiology, Immunology, & Molecular Genetics, David Geffen School of Medicine, Johnson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90025-1747


Nitric oxide (NO) is a novel cancer therapeutic, and NO donors provide a unique advantage in the study of the properties of NO as an anti-neo-plastic agent because they exhibit novel anti-tumor sensitizing abilities and reverse resistance to cytotoxic therapies. We present evidence on the enhancement by NO, used in combination with chemotherapy, of drug-induced apoptosis in colorectal cancer cells and NO-mediated regression of tumor xenografts resistant to conventional chemo- and radiotherapeutic interventions. Treatment with (Z)-l-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-l-ium-1,2-diolate (DETANONOate) sensitized SW620 metastatic CRC cells to cisplatin (CDDP)-induced apoptosis. Nude mice bearing SW620 xenografts treated with CDDP and DETANONOate demonstrated a 36% reduction in tumor load compared with control, and this was associated with an up-regulation of the expression of the apoptosis-inducing factor (AIF). Similarly, in models of rectal cancer, pretreating radio-resistant HT-29 colorectal cancer cells with DETANONOate for 16 h prior to ionizing radiation resulted in a significant reduction in colony formation (47%) compared with DETANONOate treatment alone. In vivo, SCID mice bearing HT-29 xenografts and treated with irradiation, DETANONOate, or a combination showed tumor growth reduction by 32.5% following the combination treatment. In vitro, the sensitizing activity of DETANONOate was associated with an up-regulation of p21, p27, and BAX, with a concomitant decrease in Bcl-2 expression in DETANONOate-pretreated HT-29 cells compared with controls. Altogether, these results demonstrate that DETANONOate is a potent chemo-radio-sensitizer in colorectal cancer cells that are resistant to conventional chemo- and radiotherapies.

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