Up-regulation of human prostaglandin reductase 1 improves the efficacy of hydroxymethylacylfulvene, an antitumor chemotherapeutic agent.
Prostaglandin reductase 1 (PTGR1) is a highly inducible enzyme with enone reductase activity. Previous studies demonstrated the role of rat PTGR1 in the activation of acylfulvene analogs, a class of antitumor natural product derivatives. Of these, hydroxymethylacylfulvene (HMAF) was in advanced clinical development for the treatment of advanced solid tumors, including prostate, ovarian, and pancreatic cancers. However, the efficiency of human PTGR1 in activating acylfulvenes and its potential to enhance therapeutic efficacy have remained uncharacterized. In this study, human PTGR1 was polymerase chain reaction-cloned and purified. Conversion of HMAF to its cellular metabolite by the purified enzyme proceeded at a 20-fold higher rate than with the rat variant of the enzyme. The Km was 4.9 μM, which was 40-fold lower than for the rat variant and similar to the therapeutic dose. Human cell lines, including colon cancer lines, were transfected with a vector containing rat PTGR1 or human PTGR1, and cell viability was examined after dosing with HMAF. New data obtained in this study suggest that transfection with human PTGR1, or its induction in colon and liver cancer cell lines with 1,2-dithiol-3-thione, enhances susceptibility to the cytotoxic influences of HMAF by 2- to 10-fold. Furthermore, similar or enhanced enzyme induction and HMAF toxicity results from preconditioning cancer cells with the bioactive food components curcumin and resveratrol. The functional impact of PTGR1 induction in human cells and chemical-based strategies for its activation can provide important knowledge for the design of clinical strategies involving reductively activated cytotoxic chemotherapeutics.
Cancer Cell and Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. xshawnyu@gmail.com
Xiang
X
Yu
Melanie M
MM
Erzinger
Kathryn E
KE
Pietsch
Frances N
FN
Cervoni-Curet
John
J
Whang
John
J
Niederhuber
Shana J
SJ
Sturla
D011452:15-Oxoprostaglandin 13-Reductase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D061745:Antioxidant Response Elements; D000975:Antioxidants / Q000494:pharmacology; D001711:Biotransformation / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003001:Cloning, Molecular; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D007700:Kinetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D012717:Sesquiterpenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology
D018906:Antineoplastic Agents, Alkylating; D000975:Antioxidants; D007202:Indicators and Reagents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011994:Recombinant Proteins; D012717:Sesquiterpenes; C102714:irofulven; D011452:15-Oxoprostaglandin 13-Reductase