DETANONOate is a potent chemo\radio-sensitizing agent in colon and colorectal cancers as assessed in in vitro and in vivo established tumor xenografts

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 antineoplastic 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-1-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.