Thus, it is possible that the observed enhancement of miRNA production upon enoxacin treatment is mediated by a direct effect of the drug on the TRBP protein.Indeed, we have identied a physical interaction between enoxacin and the TRBP protein by using two independent methods, surface plasmon resonance and isothermal Aspirin titration calorimetry.By following the description above of the antiproliferative effect of enoxacin in cultured cancer cells, we translated these results to in vivo animal tumor models.We found that the implanted colorectal cancer cell lines RKO and HCT showed potent tumorgrowth inhibition upon enoxacin use as indicated by tumor weight. We next conducted a pathological examination of all xenografted Famciclovir tumors with the different enoxacin and control treatments.Most importantly, at the time of sacrice, colon, lung, liver, and kidney tissues were resected for pathological analysis and no toxicity was detected in any of the mice used in the assay. We wondered whether enoxacin also promoted miRNA processing in the described xenografted nude mice model.We then decided to investigate the role of enoxacin in the metastatic process of distal seeding and growth in the two main organs affected by colorectal cancer dissemination.The establishment of suitable mouse models of cancer showing humanlike tumor progression is essential to develope unique therapeutic approaches.Thus, we complemented our enoxacin in vivo mouse studies by generating orthotopic models of implanted human primary colorectal tumors.Seven MSI tumors were identied from a previously established collection of human primary colorectal tumors.The seven MSI colorectal tumors were genetically screened for mutations in TARBP and one repeat in exon that creates a premature stop codon and truncates TRBP. The mutation was heterozygous and associated with a decrease in TRBP protein levels. When the seven MSI tumors were orthotopically reimplanted in the ceacum of three nude mice per patient, only three tumors grew: two TARBP wildtype. Tissue samples from the tumors were also collected for analysis of miRNA expression proles.As expected, a signicant downregulation of the corresponding precursor miRNA molecules upon enoxacin use was only observed in CRC and CRC wildtype TRBP tumors to analyze two primary human orthotopically transplanted tumors. Covalent modications of the analog inhibitor include locked nucleic acids. Alternatively, it is possible to use a sponge vector expressing miRNA target sites to saturate the endogenous miRNA. Similar results have recently been obtained in a mouse model of lung cancer and xenografted prostate tumors for the exogenous delivery of let and miR, respectively. This is the same line of reasoning as for DNA demethylating agents and histone deacetylase inhibitors that, even without the existence of any target specicity, have received clinical approval for the treatment of certain hematological malignancies. Enoxacin belongs to the family of synthetic antibacterial compounds based on a uoroquinolone skeleton that are relatively nontoxic and inhibit type II DNA topoisomerase in mammalian cells and bacterial DNA gyrase.Enoxacin has been used to treat bacterial infections such as urinary tract infections. SB were erroneously graphed because of the same error with the formula.The corrected figures and their legends appear below.The figures in the supplemental information have also been corrected.

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