Intratumoral injection of oligonucleotides to the NFκB binding site inhibits cachexia in a mouse tumor model

Abstract

Cancer cachexia, characterized by anorexia, weight loss muscle mass and food intake, which were induced by the and progressive tissue wasting, has been postulated to be tumor presence. Interleukin 6 mRNA in the tumor was also mediated by various cytokines. However, the precise markedly decreased by the transfection of NF B decoy mechanism of cachexia induction is not fully explained. We ODN. It is known that the transcriptional factor E2F plays have developed synthetic double-stranded oligodeoxynua pivotal role in the coordinated transactivation of cell cycle cleotides (ODN) as 'decoy' cis-elements that block the regulatory genes. Therefore, we hypothesized that the binding of nuclear factors to promoter regions of targeted introduction of synthetic double-stranded DNA with high genes, resulting in the inhibition of gene transactivation in affinity for E2F in vivo as 'decoy' cis-elements might inhibit vivo as well as in vitro. This novel molecular strategy could the tumor growth of colon26, resulting in turn in inhibition of be useful for treating a broad range of human diseases cachexia induction. However, injection of E2F decoy ODN including cancer. In this study, we injected decoy ODN tarfailed to inhibit tumor growth and cachexia induction, as geting the transcriptional factor, NF-kappaB (NF B) bindcompared with mismatched decoy ODN. Overall, the ing cis-elements, which are essential for transactivation of present study demonstrated that cachexia induced by gene expression of cytokines, directly into tumors of adenocarcinoma colon26 was inhibited by blocking of adenocarcinoma colon26 in mice, in order to examine NF B, using a novel molecular decoy strategy, without an whether or not cachexia is alleviated by inhibiting the action effect on tumor growth, and also that tumor growth and of cytokines. Tumor growth was not affected by transfeccachexia induction in the colon26 model were not affected tion of NF B decoy ODN as compared with scrambled by E2F decoy ODN. These results suggest that cytokines decoy ODN. Nevertheless, transfection of NF B decoy, but regulated by NF B may play a pivotal role in the induction not scrambled decoy, ODN resulted in attenuation of the of cachexia by colon26, providing a new therapeutic reductions in body weight, epididymal fat, gastrocnemius strategy for cancer cachexia.

Prevention and regression of atopic dermatitis by ointment containing NF-kB decoy oligodeoxynucleotides in NC/Nga atopic mouse model

“…transcription factor. [11][12][13][14][15]30 Synthetic ODN were washed with 70% ethanol, dried and dissolved in sterile Tris-EDTA buffer (10 mM Tris, 1 mM EDTA). The supernatant was purified over a NAP 10 column (Pharmacia, Uppsala, Sweden), and quantitated by spectrophotometry.…”

“…9,10 Therefore, the decoy approach enables us to treat diseases by modulating endogenous transcriptional regulation. [11][12][13][14][15] We hypothesized that the skin's allergic response in atopic dermatitis might be improved by the transfection of NF-kB decoy ODN. If the expression of cytokines and adhesion molecules involved in the development of atopic skin conditions, the most important step in the process of atopic dermatitis might be suppressed by NF-kB decoy ODN in vivo.…”

Transfection of NF-κB decoy oligodeoxynucleotide suppresses pulmonary metastasis by murine osteosarcoma

“…The NF-kB decoy ODN strategy has been applied to various diseases, such as re-stenosis after angioplasty or stenting, glomerulonephritis, rheumatoid arthritis and atopic dermatitis (see review 19 ). In oncology, it has been reported that the intra-tumor injection of NF-kB decoy ODN inhibited the cachexia induced by adenocarcinoma 20 and that intravenous treatment with NF-kB decoy ODN inhibited the hepatic metastasis of M5076 reticulosarcoma in mice. 21 Therefore, we hypothesized that transfection with NF-B decoy ODN would suppress the tumor growth and pulmonary metastases of osteosarcoma.…”

Local administration of transcription factor decoy oligonucleotides to nuclear factor-κB prevents carrageenin-induced inflammation in rat hind paw

“…29 The decoy strategy has recently been developed 30 and is considered a useful tool for analyzing the blockade of the expression of a wide variety of NF-B-dependent proinflammatory mediators. 31,32 Recent evidence has demonstrated that synthetic double stranded ODN as decoy cis elements block the binding of NF-B to promoter regions of its targeted genes, resulting in the inhibition of gene transactivation in vitro [33][34][35] and in vivo. 31,32 An alternative approach utilizes a cell-permeable peptide, called SN-50, carrying a functional domain NLS capable of inhibiting the nuclear translocation of NF-B complexes.…”