Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Abstract

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 K m was 4.9 M, 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.

Modulation of Nitro-fatty Acid Signaling

“…Notably, PtGR-1 was induced in HepG2 cells upon treatment with NO 2 -OA (Fig. 8), consistent with previous work showing that electrophiles efficiently induce PtGR-1 in these and other cell lines (65). Furthermore, global gene expression studies of human endothelial cells showed that PtGR-1 is among the top four transcripts induced upon treatment with NO 2 -OA (18).…”

Induction of Complementary Function Reductase Enzymes in Colon Cancer Cells by Dithiole‐3‐thione versus Sodium Selenite

“…By combining D3T pretreatment with HMAF, a significant increase in cytotoxicity of the drug was detected. In another study, pretreating HepG2 or SW620 cells with curcumin, resveratrol, or D3T reduced IC 50 values for HMAF to a larger extent [38]. In the earlier case, however, PTGR1 was induced up to fourfold [38].…”

“…In another study, pretreating HepG2 or SW620 cells with curcumin, resveratrol, or D3T reduced IC 50 values for HMAF to a larger extent [38]. In the earlier case, however, PTGR1 was induced up to fourfold [38]. Furthermore, the sensitivity of HeLa cells toward acylfulvenes was increased about 50% upon selenite preconditioning, which was associated with a fourfold induction of TrxR1 [35].…”

Improved Efficacy of Acylfulvene in Colon Cancer Cells When Combined with a Nuclear Excision Repair Inhibitor

“…Thus, AFs are bioactivated by prostaglandin reductase 1 (PTGR1) resulting in an activated intermediate that can react with DNA, and sensitive cancer cells have higher PTGR1 activity and/or expression levels. 4,5,6 While selective bioactivation appears to enhance selectivity, drug resistance may arise from the DNA damage response. 7,8 .…”