Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent
| Autor: | Kathryn E. Pietsch, Frances N. Cervoni-Curet, Melanie M. Erzinger, John E. Niederhuber, Shana J. Sturla, Xiang Yu, John Whang |
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| Rok vydání: | 2012 |
| Předmět: |
Acylfulvene
Cell Survival NF-E2-Related Factor 2 Blotting Western Biology Enone reductase activity Polymerase Chain Reaction Antioxidants chemistry.chemical_compound Therapeutic index Cell Line Tumor Animals Humans Viability assay Cloning Molecular Enzyme inducer 15-Oxoprostaglandin 13-Reductase Promoter Regions Genetic Antineoplastic Agents Alkylating Biotransformation Pharmacology Transfection Chemotherapy Antibiotics and Gene Therapy Antioxidant Response Elements Recombinant Proteins Rats Up-Regulation Kinetics chemistry Biochemistry Enzyme Induction Cancer cell Curcumin Cancer research biology.protein Molecular Medicine Indicators and Reagents Sesquiterpenes Plasmids |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 343:426-433 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.112.195768 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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