Sujet(s)
Anticoagulants/administration et posologie , Essais cliniques comme sujet , Warfarine/administration et posologie , Administration par voie orale , Anticoagulants/effets indésirables , Agrément de médicaments/méthodes , Facteur Xa , Inhibiteurs du facteur Xa/usage thérapeutique , Humains , Pyrazoles/usage thérapeutique , Pyridones/usage thérapeutique , Protéines recombinantes , Rivaroxaban/usage thérapeutiqueRÉSUMÉ
Here we report the radiosynthesis of an endogenous redox pair, [(11)C]ascorbic acid ([(11)C]VitC) and [(11)C]dehydroascorbic acid ([(11)C]DHA), the reduced and oxidized forms of vitamin C, and their application to ROS sensing. These results provide the basis for in vivo detection of ROS using positron emission tomography (PET).
Sujet(s)
Acide ascorbique/composition chimique , Radio-isotopes du carbone/composition chimique , Tomographie par émission de positons , Espèces réactives de l'oxygène/analyse , OxydoréductionSujet(s)
Neurosciences , Soins , Périodiques comme sujet , Internet , Périodiques comme sujet/tendances , Médias sociauxSujet(s)
Anticoagulants/administration et posologie , Thrombose/soins infirmiers , Thrombose/prévention et contrôle , Warfarine/administration et posologie , Administration par voie orale , Anticoagulants/effets indésirables , Benzimidazoles/administration et posologie , Benzimidazoles/effets indésirables , Dabigatran , Agrément de médicaments , Humains , Morpholines/administration et posologie , Morpholines/effets indésirables , Pyrazoles/administration et posologie , Pyrazoles/effets indésirables , Pyridones/administration et posologie , Pyridones/effets indésirables , Rivaroxaban , Thiophènes/administration et posologie , Thiophènes/effets indésirables , Warfarine/effets indésirables , bêta-Alanine/administration et posologie , bêta-Alanine/effets indésirables , bêta-Alanine/analogues et dérivésRÉSUMÉ
The DNA-damaging agent camptothecin (CPT) and its analogs demonstrate clinical utility for the treatment of advanced solid tumors, and CPT-based nanopharmaceuticals are currently in clinical trials for advanced kidney cancer; however, little is known regarding the effects of CPT on hypoxia-inducible factor-2α (HIF-2α) accumulation and activity in clear cell renal cell carcinoma (ccRCC). Here we assessed the effects of CPT on the HIF/p53 pathway. CPT demonstrated striking inhibition of both HIF-1α and HIF-2α accumulation in von Hippel-Lindau (VHL)-defective ccRCC cells, but surprisingly failed to inhibit protein levels of HIF-2α-dependent target genes (VEGF, PAI-1, ET-1, cyclin D1). Instead, CPT induced DNA damage-dependent apoptosis that was augmented in the presence of pVHL. Further analysis revealed CPT regulated endothelin-1 (ET-1) in a p53-dependent manner: CPT increased ET-1 mRNA abundance in VHL-defective ccRCC cell lines that was significantly augmented in their VHL-expressing counterparts that displayed increased phosphorylation and accumulation of p53; p53 siRNA suppressed CPT-induced increase in ET-1 mRNA, as did an inhibitor of ataxia telangiectasia mutated (ATM) signaling, suggesting a role for ATM-dependent phosphorylation of p53 in the induction of ET-1. Finally, we demonstrate that p53 phosphorylation and accumulation is partially dependent on mTOR activity in ccRCC. Consistent with this result, pharmacological inhibition of mTORC1/2 kinase inhibited CPT-mediated ET-1 upregulation, and p53-dependent responses in ccRCC. Collectively, these data provide mechanistic insight into the action of CPT in ccRCC, identify ET-1 as a p53-regulated gene and demonstrate a requirement of mTOR for p53-mediated responses in this tumor type.