The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3.
PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) family members whose expressions correlated with aerobic metabolism of PR-104A. Plasmid-based expression of candidate genes identified aldo-keto reductase 1C3 as a novel nitroreductase. AKR1C3 protein was detected by Western blot in 7 of 23 cell lines and correlated with oxic PR-104A metabolism, an activity which could be partially suppressed by Nrf2 RNAi knockdown (or induced by Keap1 RNAi), indicating regulation by the ARE pathway. AKR1C3 was unable to sensitize cells to 10 other bioreductive prodrugs and was associated with single-agent PR-104 activity across a panel of 9 human tumor xenograft models. Overexpression in two AKR1C3-negative tumor xenograft models strongly enhanced PR-104 antitumor activity. A population level survey of AKR1C3 expression in 2,490 individual cases across 19 cancer types using tissue microarrays revealed marked upregulation of AKR1C3 in a subset including hepatocellular, bladder, renal, gastric, and non-small cell lung carcinoma. A survey of normal tissue AKR1C3 expression suggests the potential for tumor-selective PR-104A activation by this mechanism. These findings have significant implications for the clinical development of PR-104.
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Auckland, New Zealand.
Christopher P
CP
Guise
Maria R
MR
Abbattista
Rachelle S
RS
Singleton
Samuel D
SD
Holford
Joanna
J
Connolly
Gabi U
GU
Dachs
Stephen B
SB
Fox
Robert
R
Pollock
Justin
J
Harvey
Parry
P
Guilford
Fernando
F
Doñate
William R
WR
Wilson
Adam V
AV
Patterson
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000332:Aerobiosis / Q000502:physiology*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009588:Nitrogen Mustard Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D009588:Nitrogen Mustard Compounds; C524170:PR-104A; D011355:Prodrugs; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D010100:Oxygen