Marked regression of liver metastasis by combined therapy of ultrasound-mediated NFkB-decoy transfer and transportal injection of paclitaxel, in mouse


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Abstract

Nuclear factor-kappaB (NFkB) plays a pivotal role in cancer progression. In this study, we developed a decoycis-element oligo-deoxyribonucleic acid against NFkB-binding site (NFkB-decoy), which effectively inhibits NFkB activity, and tested the effect of combined therapy comprising local transfection of NFkB-decoy into the liver and transportal injection of paclitaxel on cancer growth and metastasis using an orthotopic murine model of colon cancer liver metastasis. For NFkB-decoy transfection, we employed a novel approach using ultrasound exposure with an echocardiographic contrast agent, Optison. We examined the influence of NFkB-decoy transfer on susceptibility to paclitaxel in cancer cells and the mechanism involved using severalin vitroanalysis systems. We then studied thein vivoeffect of combined NFkB-decoy transfer and paclitaxel in preventing cancer progression using a murine model of liver metastasis created by splenic injection of a human colon cancer cell line, HT29.In vitroexperiments, including MTT-assay, fluorescence-activated cell sorter and cDNA array analysis, revealed that NFkB-decoy transfer significantly increased the susceptibility of cancer cells to paclitaxel, and that decreased expression of anti-apoptotic genes along with increased expression of genes relevant to the apoptosis-promotor may be involved.In vivoexperiments showed that local transfection of NFkB-decoy into the liver followed by portal injection of paclitaxel effectively induced cancer cell apoptosis in the liver metastasis, and significantly prolonged animal survival compared to controls, without notable side effects. In conclusion, a combination of local NFkB-decoy transfer into the liver and transportal injection of paclitaxel may be a safe and effective new therapy for liver metastasis.

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