Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor
Anna Skwarska, Ewen D. D. Calder, Deborah Sneddon, Hannah R. Bolland, Maria L. Odyniec, Ishna N. Mistry, Jennifer Martin, Lisa K. Folkes, Stuart J. Conway, Ester M. Hammond
Abstract
). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub-micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.
Topics & Concepts
PanobinostatHypoxia (environmental)Clonogenic assayProdrugAcetylationPharmacologyCancer researchApoptosisHistone deacetylase inhibitorPharmacokineticsMedicineChemistryHistone deacetylaseHistoneBiochemistryOxygenOrganic chemistryGeneHistone Deacetylase Inhibitors ResearchAutophagy in Disease and TherapyAdenosine and Purinergic Signaling