Highlights d A pan-tissue AHR signature identifies IL4I1 as a major AHRactivating enzyme d IL4I1-mediated Trp catabolism yields indoles and kynurenic acid that activate the AHR d IL4I1 promotes AHR-driven cancer cell motility and suppresses adaptive immunity d IL4I1 enhances CLL progression and is induced by immune checkpoint blockade
For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene-amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation-inducing agents.
Large quantities of fluoroquinolone carboxylic acid (FQCA) derivatives are applied as antibacterial agents in large-scale animal husbandry. Important quantities are transported to agricultural areas by means of liquid manure. The binding of FQCA derivatives to clay minerals and their sorption by five soils from different geographic areas were investigated. Sorption was studied in batch experiments using radioactive labeled enrofloxacin (Baytril), decarboxylated enrofloxacin, ciprofloxacin (Cyprobay), levofloxacin (Oxaldin), and a fluorochloroquinolone carboxylic acid derivative. More than 90% (K D ) 260-5612) of the applied enrofloxacin adsorbed on the different soils. The other chemicals showed a similar adsorption (K D ) 285-496) on a German soil except the decarboxylated enrofloxacin (K D ) 7.7). At clay minerals enrofloxacin was adsorbed >98%. X-ray diffraction analysis showed that the adsorption at the clay mineral montmorillonite occurred between the layers, resulting in an expansion of the spacing. Microcalorimetric and infrared measurements confirmed an electrostatic interaction between the adsorbed chemical and the adsorbent.
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