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.
Highlights
The Brain Blood Barrier (BBB) protects central nervous system (CNS) against chemical and biological insults
It seems that these glutathione S-transferases (GST), mainly the GSTP1 (GST-π) isoform, which is the most abundant at the BBB, protect cells against oxidative stress and are involved in the phenomenon of drug resistance (Shawahna et al, 2013)
It was documented that GST-π polymorphisms are associated with survival in anaplastic glioma patients; an explanation is that lower activity GST genotypes will allow more prolonged
Summary
The Brain Blood Barrier (BBB) protects central nervous system (CNS) against chemical and biological insults It was described as composed mainly of highly specialized endothelial cells with tight junctions, and astrocyte endfeets with anchoring transmembrane proteins (Bentivoglio and Kristensson, 2014). Glutathione S-transferases (GST; EC 2.5.1.18), multifunctional enzymes which are mainly involved in phase II metabolism and antioxidant cell systems (Di Pietro et al, 2010), are among the drug-metabolizing enzymes present in BBB It seems that these GSTs, mainly the GSTP1 (GST-π) isoform, which is the most abundant at the BBB, protect cells against oxidative stress and are involved in the phenomenon of drug resistance (Shawahna et al, 2013). It was documented that GST-π polymorphisms are associated with survival in anaplastic glioma patients; an explanation is that lower activity GST genotypes will allow more prolonged
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