Diêgo Madureira de Oliveira, Marcel Tavares de Farias, André Lacerda Braga Teles, Manoelito Coelho dos Santos, Martins Dias de Cerqueira, Rute Maria Ferreira Lima, Ramon Santos El-Bachá
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.
Pharmacology, Toxicology and Pharmaceutical Science
5
11%
Agricultural and Biological Sciences
5
11%
Medicine and Dentistry
4
9%
Chemistry
3
7%
Other
9
20%
Unknown
7
16%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 18 October 2014.
All research outputs
#20,239,689
of 22,766,595 outputs
Outputs from Frontiers in Cellular Neuroscience
#3,561
of 4,228 outputs
Outputs of similar age
#211,217
of 252,704 outputs
Outputs of similar age from Frontiers in Cellular Neuroscience
#57
of 87 outputs
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