8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1

Abstract

The blood-brain barrier (BBB) is known to protect healthy brain cells from potentially dangerous chemical agents, but there are many evidences supporting the idea that this protective action is extended to tumor cells. Since the process of angiogenesis in brain tumors leads to BBB breakdown, biochemical characteristics of the BBB seem to be more relevant than physical barriers to protect tumor cells from chemotherapy. In fact, a number of resistance related factors were already demonstrated to be component of both BBB and tumor cells. The enzyme glutathione S-transferases (GST) detoxify electrophilic xenobiotics and endogenous secondary metabolites formed during oxidative stress. A role has been attributed to GST in the resistance of cancer cells to chemotherapeutic agents. This study characterized 8-methoxypsoralen (8-MOP) as a human GST P1-1 (hGST P1-1) inhibitor. To identify and characterize the potential inhibitory activity of 8-MOP, we studied the enzyme kinetics of the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) with GSH catalyzed by hGST P1-1. We report here that 8-MOP competitively inhibited hGST P1-1 relative to CDNB, but there was an uncompetitive inhibition relative to GSH. Chromatographic analyses suggest that 8-MOP is not a substrate. Molecular docking simulations suggest that 8-MOP binds to the active site, but its position prevents the GSH conjugation. Thus, we conclude that 8-MOP is a promising prototype for new GST inhibitors pharmacologically useful in the treatment of neurodegenerative disorders and the resistance of cancer to chemotherapy.

p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance

“…Furthermore, high GSH pool levels or elevated expression of GSTP1, GSTZ1, or other glutathione pathway genes could serve as biomarkers for the stratification patients. In this study, we used BSO, an inhibitor of GCL, to deplete the GSH pool, but specific inhibitors of GSTP1 such as 8-methoxypsoralen are currently under development (51). The use of agents to deplete the GSH pool in combination with conventional therapeutics or molecularly targeted drugs thus warrants further study in high-risk neuroblastoma.…”

The classical photoactivated drug 8-methoxypsoralen and related compounds are effective without UV light irradiation against glioma cells

“…We found that a 72-h incubation with 0.4 mM 8-MOP promoted death on 41.68% of human glioblastoma GL-15 cells. Indeed, in our study 0.2 mM 8-MOP was more effective against GL-15 cells, which are extremely resistant to TMZ (de Oliveira et al, 2014), than 0.2 mM TMZ against GOS-3 and U-87 MG glioma cells (Patel et al, 2008).…”

“…This effect is probably due to the antiproliferative action of 8-MOP, since the reduction of cell density in the culture is itself a stimulus for vimentin expression, which also occurs after treatment with traditional chemotherapy (Trog et al, 2008). We have recently demonstrated that 8-MOP also inhibits the glutathione S-transferase p (GSTP1) activity and increases cell susceptibility to apoptosis (de Oliveira et al, 2014), which could explain the proapoptotic action of 8-MOP at high concentrations.…”

A tyrosine-reactive irreversible inhibitor for glutathione S-transferase Pi (GSTP1)

“…Many GSH analogs, small-molecules and natural products have been generated as GSTP1 inhibitors. 2 Reversible GSTP1 inhibitors include 8-methoxypsoralen, piperlongumine, aloe emodin, and benstatin A, 2, 6, 7 as well as Telintra (Ezatiostat), which is currently in clinical trials for the treatment of myelodysplastic syndrome. 8, 9 GSTP1 contains four cysteine residues, two of which (C47 and C101) have been shown to be highly reactive and targeted by irreversible GSTP1 inhibitors.…”