6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol: a promising new anticancer compound

Abstract

The 7-nitro-2,1,3-nitrobenzoxadiazole (NBD) derivatives are a series of compounds containing the NBD scaffold that are not glutathione (GSH) peptidomimetics, and result in a strong inhibition of glutathione S-transferases (GSTs). Growing evidences highlight their pivotal roles and outstanding anticancer activity in different tumor models. In particular, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) is extensively studied, which is a very efficient inhibitor of GSTP1-1. It triggers apoptosis in several tumor cell lines and this cytotoxic activity is observed at micro and submicromolar concentrations. Importantly, studies have shown that NBDHEX acts as an anticancer drug by inhibiting GSTs catalytic activity, avoiding inconvenience of the inhibitor extrusion from the cell by specific pumps and disrupting the interaction between the GSTP1-1 and key signaling effectors. Additionally, some researchers also have discovered that NBDHEX can act as late-phase autophagy inhibitor, which opens new opportunities to fully exploit its therapeutic potential. In this review, we summarize the advantages, anticancer mechanisms, and analogs of this compound, which will establish the basis on the usage of NBDHEX in clinical applications in future.

Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors

“…This molecule is also considered a highly efficient GST suicide inhibitor, due to its ability to bind in the substrate binding site (H-site) of GSTP1 and form a complex with GSH (bound in G-site), in that way inhibiting GSTP1 enzyme activity. However, lack of specificity for GSTP1 due to higher affinity for GSTM2-2, limited its clinical application, leading to synthesis of NBDHEX analogues with improved selectivity for GSTP1 [45,46,113,114,115].…”

RETRACTED ARTICLE: Silencing of Glutathione S-Transferase Pi Inhibits Cancer Cell Growth via Oxidative Stress Induced by Mitochondria Dysfunction

“…Piperlongumine and its analogs were developed with the aim of increasing cellular ROS and inducing oxidative stress by blocking GSTP 32–34 . NBDHEX, a derivative of inhibitor 7-nitro-2,1,3-nitrobenzoxadiazole for GSTs, has greatly improved substrate specificity for GSTP, and has resulted in inhibiting the interaction of GSTP with TRAF2 and JNK 35,36 . Furthermore, there are many reports suggesting that polymorphisms in GST are potentially a risk factor for some cancers as well as neurodegenerative diseases, and may be associated with drug resistance problem 10,23 .…”

In Vitro and in Vivo Efficacy of NBDHEX on Gefitinib-resistant Human Non-small Cell Lung Cancer

“…Among these, NBDHEX has been shown recently to be a promising anticancer drug 20 , 24 , 42 , 43 . However, the usefulness of NBDHEX in NSCLC gefitinb-resistance has been unexplored 25 . To evaluate the effects of NBDHEX, HCC827/GR cells were treated with various concentrations of the drug.…”

“…Recently, NBDHEX was shown to act as a late phase autophagy inhibitor, which provides a new avenue by which to explore its therapeutic potential [24]. We previously summarized NBDHEX's promising anticancer effects on various cancer cell lines and in animal models of osteosarcoma, small cell lung cancer, and acute myeloid leukemia [25]. However, the effect of NBDHEX on GSTpi in gefitinib-resistant NSCLC remains unexplored.…”