Hunter 2012 Biochem Pharmacol

[[Has title::Hunter FW, Wang J, Patel R, Hsu HL, Hickey AJ, Hay MP, Wilson WR (2012) Homologous recombination repair-dependent cytotoxicity of the benzotriazine di-N-oxide CEN-209: Comparison with other hypoxia-activated prodrugs. Biochem Pharmacol 83:574–85.]]

» [[Has info::PMID: 22182429]]

Was written by::Hunter FW, Was written by::Wang J, Was written by::Patel R, Was written by::Hsu HL, Was written by::Hickey AJ, Was written by::Hay MP, Was written by::Wilson WR (Was published in year::2012) Was published in journal::Biochem Pharmacol

Abstract: [[has abstract::CEN-209 (SN30000) is a second-generation benzotriazine di-N-oxide currently in advanced preclinical development as a hypoxia-activated prodrug (HAP). Herein we describe the DNA repair-, hypoxia- and one-electron reductase-dependence of CEN-209 cytotoxicity. We deployed mutant CHO cell lines to generate DNA repair profiles for CEN-209, and compared the profiles with those for other HAPs. Hypoxic selectivity of CEN-209 was significantly greater than PR-104A and the nitro-chloromethylbenzindoline (nCBI/SN29428) and comparable to tirapazamine and TH-302. CEN-209 was selective for homologous recombination (HR) repair-deficient cells (Rad51d−/−), but less so than nitrogen mustard prodrugs TH-302 and PR-104A. Further, DNA repair profiles for CEN-209 differed under oxic and hypoxic conditions, with oxic cytotoxicity more dependent on HR. This feature was conserved across all three members of the benzotriazine di-N-oxide class examined (tirapazamine, CEN-209 and CEN-309/SN29751). Enhancing one-electron reduction of CEN-209 by forced expression of a soluble form of NADPH:cytochrome P450 oxidoreductase (sPOR) increased CEN-209 cytotoxicity more markedly under oxic than hypoxic conditions. Comparison of oxygen consumption, H2O2 production and metabolism of CEN-209 to the corresponding 1-oxide and nor-oxide reduced metabolites suggested that enhanced oxic cytotoxicity in cells with high one-electron reductase activity is due to futile redox cycling. This study supports the hypothesis that both oxic and hypoxic cell killing by CEN-209 is mechanistically analogous to tirapazamine and is dependent on oxidative DNA damage repaired via multiple pathways. However, HAPs that generate DNA interstrand cross-links, such as TH-302 and PR-104, may be more suitable than benzotriazine di-N-oxides for exploiting reported HR repair defects in hypoxic tumour cells.]] • Keywords: has publicationkeywords::CHO cells

• O2k-Network Lab: Was published by MiPNetLab::NZ Auckland Hickey AJ

Correction

An Oroboros O2k was used in this publication, whereas the Anton Paar/Oroboros Oxygraph was the first-generation instrument for high-resolution respirometry, which was replaced by the Oxygraph-2k in 2002.

• Further details: Gnaiger 2012 Abstract Bioblast-Gentle Science

Labels: MiParea: MiP area::Respiration, MiP area::Pharmacology;toxicology 

Stress:Injury and adaptation::Oxidative stress;RONS 

Tissue;cell: tissue and cell::CHO  Preparation: Preparation::Intact cells 

HRR: Instrument and method::Oxygraph-2k, Instrument and method::O2k-Fluorometer