Identification of phenazine analogue as a novel scaffold for thioredoxin reductase I inhibitors against Hep G2 cancer cell lines

Abstract

Even though phenazines have been extensively reported as anticancer molecules, the molecular target of these compounds is severely lagging behind. Our study consequently focuses on the anticancer target of a phenazine analogue ( CPUL1 ) for its potently antitumor activities in initial stage. Along with redox status courses of Hep G2 cells, thioredoxin reductase I (TrxR1) was speculated as anticancer target of CPUL1 . By virtue of zymologic, immunological and molecular biological experiments, we demonstrated that TrxR1 could be the anticancer target of CPUL1 . The knowledge on phenazine targeting to TrxR1 have not been reported previously. Thus, it can provide valuable information for further development of the TrxR1 inhibitors.

Novel Chalcone‐Phenazine Hybrids Induced Ferroptosis in U87‐MG Cells through Activating Ferritinophagy

“…Recently, based on the strategy of molecular hybridization, our group successfully screened out pyran‐phenazine hybrid molecules CPUL129 and CPUL149 ( Figure 1) from the phenazine library established by us before [11–18] . These compounds could accumulate and sequester iron in lysosomes through interacting with iron and regulating the expression of proteins (IRP2, TfR1, ferritin) engaged in iron transport and strorage, eventually specifically inhibit the stemness of breast cancer cells through triggering ferroptosis [19] …”

Nanoaggregates of Disulfide-Decorated TrxR Inhibitor Promote Cellular Uptake, Selective Targeting, and Antitumor Efficacy

“…In previous work, we successfully screened out a novel TrxR inhibitor CPUL1 from the compound library established by our group before, − but poor water solubility greatly limits its further antitumor application. In recent years, carrier-free nanomedicine completely composed of active pharmaceuticals has attracted a lot of attention. − We recently used carrier-free, mitochondria-targeting strategy to prepare self-assembled nanoaggregates (CPUL1-TPP NAs) composed of CPUL1 and a triphenylphosphine (TPP) derivative through electrostatic and π–π stacking interactions, with the aim to enhance antitumor efficacy of insoluble CPUL1 on HUH7 hepatoma cells as well as meliorate drug solubility and enhance intracellular drug accumulation in cytoplasm.…”

Development and validation of a liquid chromatography‐tandem mass spectrometry method for CPUL1, a novel antitumor candidate compound, and its application to pharmacokinetic studies

“…As one of the synthetic phenazines, the active substance of pyrano [3,2-a]phenazine, also called CPUL1 (Figure S1B), has shown high inhibitory effects on various tumor cells, including gastric, liver, and breast cancers [5][6][7]. Furthermore, CPUL1 displayed the best antiproliferative activity against HepG2 cancer cells without obvious cytotoxicity against human normal liver epithelial L02 cells, suggesting a better safety potential [8,9]. Further pharmacological mechanistic studies revealed that CPUL1 inhibited topoisomerase I/II, promoted GSH depletion, and induced apoptosis through a mitochondrial-dependent pathway.…”

“…Further pharmacological mechanistic studies revealed that CPUL1 inhibited topoisomerase I/II, promoted GSH depletion, and induced apoptosis through a mitochondrial-dependent pathway. Moreover, CPUL1 acted as a thioredoxin reductase 1 (TrxR1) inhibitor and activated apoptosis through the ROS-Trx-ASK1-p38 pathway [7][8][9]. Thus, CPUL1 was regarded as a promising anticancer candidate compound.…”