Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells.

Peroxiredoxin (PRDX1) is a tumor-overexpressed antioxidant enzyme for eliminating excessive reactive oxygen species (ROS) to protect tumor cells from oxidative damage. Herein, a series of celastrol urea derivatives were developed based on its cocrystal structure with PRDX1, with the aim of pursuing a PRDX1-specific inhibitor. Among them, derivative 15 displayed potent anti-PRDX1 activity (IC50 = 0.35 µM) and antiproliferative potency against colon cancer cells. It covalently bound to Cys-173 of PRDX1 (KD = 0.37 µM), which was secured by the cocrystal structure of PRDX1 with an analogue of 15 while exhibiting weak inhibitory effects on PRDX2-PRDX6 (IC50 > 50 µM), indicating excellent PRDX1 selectivity. Treatment with 15 dose-dependently decreased the mitochondria membrane potential of SW620 cells, probably due to ROS induced by PRDX1 inhibition, leading to cell apoptosis. In colorectal cancer cell xenograft model, it displayed potent antitumor efficacy with superior safety to celastrol. Collectively, 15 represents a promising PRDX1 selective inhibitor for the development of anticolorectal cancer agents.

Conoidin A, a Covalent Inhibitor of Peroxiredoxin 2, Reduces Growth of Glioblastoma Cells by Triggering ROS Production.

Compounds that cause oxidative stress have recently gained considerable interest as potential anticancer treatment modalities. Nevertheless, their efficiency may be diminished by the antioxidant systems often upregulated in cancer cells. Peroxiredoxins (PRDXs) are antioxidant enzymes that scavenge peroxides and contribute to redox homeostasis. They play a role in carcinogenesis and are upregulated in several cancer types. Here, we assessed the expression pattern of PRDX1 and PRDX2 in glioblastoma (GBM) and examined the efficacy of their inhibitors in GBM cell lines and patient-derived GBM cells. Both PRDX1 and PRDX2 were upregulated in GBM compared to non-tumor brain tissues and their considerable amounts were observed in GBM cells. Adenanthin, a compound inhibiting PRDX1 activity, slightly decreased GBM cell viability, while conoidin A (CONA), a covalent PRDX2 inhibitor, displayed high toxicity in GBM cells. CONA elevated the intracellular reactive oxygen species (ROS) level. Pre-treatment with an ROS scavenger protected cells from CONA-induced death, indicating that ROS accumulation plays a crucial role in this phenomenon. Menadione or celecoxib, both of which are ROS-inducing agents, potentiated the anticancer activity of CONA. Collectively, our results unveil PRDX1 and PRDX2 as potential targets for GBM therapy, and substantiate the further exploration of their inhibitors.

Development of novel celastrol-ligustrazine hybrids as potent peroxiredoxin 1 inhibitors against lung cancer.

The disruption of oxidation-reduction equilibrium through inhibiting reactive oxygen species (ROS) clearance or enhancing ROS production has emerged as a novel and promising strategy for cancer therapy. Herein, a series of celastrol-ligustrazine hybrids were designed and synthesized as effective ROS promoters, and their biological activities were further evaluated. Among them, compound 7e stood out as the most potent peroxiredoxin 1 (PRDX1) inhibitor (IC50 = 0.164 µM), which was significant super to the recognized PRDX1 inhibitor Conoidin A (IC50 = 14.80 µM) and the control compound celastrol (IC50 = 1.622 µM). Furthermore, 7e dramatically promoted intracellular ROS accumulation, and inhibited the proliferation, invasion and migration of cancer cells besides inducing apoptosis in vitro. Additionally, 7e suppressed the key signaling pathways (AKT and ERK) and promoted the expression of apoptosis-related proteins (cleaved caspase-3/8 and cleaved PARP) in A549 cells, which resulted in the prevention of tumor progression. Most importantly, compound 7e (TGI = 77.47%) showed more considerable in vivo antitumor efficacy and less toxicity than celastrol (TGI = 71.00%). Overall, this work indicates 7e as the most potential PRDX1 inhibitor and may be a promising candidate for the therapy of lung cancer.

Effect of 2-Cys Peroxiredoxins Inhibition on Redox Modifications of Bull Sperm Proteins.

Sperm peroxiredoxins (PRDXs) are moonlighting proteins which, in addition to their antioxidant activity, also act as redox signal transducers through PRDX-induced oxidative post-translational modifications of proteins (oxPTMs). Despite extensive knowledge on the antioxidant activity of PRDXs, the mechanisms related to PRDX-mediated oxPTMs are poorly understood. The present study aimed to investigate the effect of bull sperm 2-Cys PRDX inhibition by Conoidin A on changes in oxPTM levels under control and oxidative stress conditions. The results showed that a group of sperm mitochondrial (LDHAL6B, CS, ACO2, SDHA, ACAPM) and actin cytoskeleton proteins (CAPZB, ALDOA, CCIN) is oxidized due to the action of 2-Cys PRDXs under control conditions. In turn, under oxidative stress conditions, 2-Cys PRDX activity seems to be focused on antioxidant function protecting glycolytic, TCA pathway, and respiratory chain enzymes; chaperones; and sperm axonemal tubulins from oxidative damage. Interestingly, the inhibition of PRDX resulted in oxidation of a group of rate-limiting glycolytic proteins, which is known to trigger the switching of glucose metabolism from glycolysis to pentose phosphate pathway (PPP). The obtained results are expected to broaden the knowledge of the potential role of bull sperm 2-Cys in both redox signal transmission and antioxidant activity.

Epo-C12 inhibits peroxiredoxin 1 peroxidase activity.

Epo-C12 is a synthetic derivative of epolactaene, isolated from Penicillium sp. BM 1689-P. Epo-C12 induces apoptosis in human acute lymphoblastoid leukemia BALL-1 cells. In our previous studies, seven proteins that bind to Epo-C12 were identified by a combination of pull-down experiments using biotinylated Epo-C12 (Bio-Epo-C12) and mass spectrometry. In the present study, the effect of Epo-C12 on peroxiredoxin 1 (Prx 1), one of the proteins that binds to Epo-C12, was investigated. Epo-C12 inhibited Prx 1 peroxidase activity. However, it did not suppress its chaperone activity. Binding experiments between Bio-Epo-C12 and point-mutated Prx 1s suggest that Epo-C12 binds to Cys52 and Cys83 in Prx 1. The present study revealed that Prx 1 is one of the target proteins through which Epo-C12 exerts an apoptotic effect in BALL-1 cells.

New substituted pyrazolones and dipyrazolotriazines as promising tyrosyl-tRNA synthetase and peroxiredoxin-5 inhibitors: Design, synthesis, molecular docking and structure-activity relationship (SAR) analysis.

New substituted pyrazolone and dipyrazolotriazine derivatives have been synthesized, designed and well characterized as promising dual antimicrobial/antioxidant agents to overcome multidrug resistant bacteria (MDR), oxidative stress and their related diseases. Among all strains, S. aureus was found to be the most susceptible for all compounds except 10b and 12b. Out of the three investigated series, sulfonamide analogues 5a-c displayed excellent antibacterial activity with 5b (MIC = 7.61 µM) and 5a (MIC = 8.98 µM) displaying activity that exceeds the reference drug tetracycline (MIC = 11.77 µM). The same sulfonamide derivatives 5a-c demonstrates high ABTS scavenging capacity comparable to standard. Moreover, the structure-activity relationship (SAR) revealed that benzenesulfonamide is a crucial group for enhancing activity. Molecular docking studies of the potent analogues were performed by targeting the crystal structures of S. aureus tyrosyl-tRNA synthetase and human peroxiredoxin-5 enzymes and the obtained results supported well the in vitro data revealing stronger binding interactions. Pharmacokinetics prediction together with modeling outcomes suggests that our sulfonamide derivatives may serve as useful lead compounds for the treatment of infectious disease.

A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in†vivo Antidiabetic and Hypolipidemic Effects.

Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds VIe and VIf bound PRDX1 and induced a dose-dependent inhibition. Furthermore, VIe and VIf significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathological examinations. These results provide guidance for developing the current FAAs as new potential antidiabetic agents.

Peroxiredoxin 2 is highly expressed in human oral squamous cell carcinoma cells and is upregulated by human papillomavirus oncoproteins and arecoline, promoting proliferation.

Peroxiredoxin 2 (PRDX2) is upregulated in various cancers including oral squamous cell carcinoma (OSCC). It is a known tumor promoter in some cancers, but its role in OSCC is unclear. This study aimed to investigate the effect of arecoline, an alkaloid of the betel nut, and human papillomavirus type 16 (HPV16) E6/E7 oncoproteins on induction of PRDX2 expression, and also the effects of PRDX2 overexpression in oral cell lines. Levels of PRDX2 protein were determined using western blot analysis of samples of exfoliated normal oral cells (n = 75) and oral lesion cells from OSCC cases (n = 75). Some OSCC cases were positive for HPV infection and some patients had a history of betel quid chewing. To explore the level of PRDX2 by western blot, the proteins were extracted from oral cell lines that were treated with arecoline or retroviruses containing HPV16 E6 gene and HPV16 E6/E7 expressing vector. For analysis of PRDX2 functions, cell proliferation, cell-cycle progression, apoptosis and migration was compared between oral cells overexpressing PRDX2 and cells with PRDX2-knockdown. PRDX2 expression levels tended to be higher in OSCC samples that were positive for HPV infection and had history of betel quid chewing. Arecoline treatment in vitro at low concentrations and overexpression of HPV16 E6 or E6/E7 in oral cells induced PRDX2 overexpression. Interestingly, in oral cells, PRDX2 promoted cell proliferation, cell-cycle progression (G2/M phase), cell migration and inhibited apoptosis. Upregulation of PRDX2 in oral cells was induced by arecoline and HPV16 oncoproteins and promoted growth of OSCC cells.

PRDX2 Promotes the Proliferation and Metastasis of Non-Small Cell Lung Cancer In Vitro and In Vivo.

PURPOSE: Previous studies have reported that the levels of PRDX2 were correlated with tumorigenicity, recurrence, and prognosis of patients with different cancers. We investigated the association between PRDX2 levels and the prognosis of lung cancer patients. We also measured PRDX2 expression of non-small cell lung cancer (NSCLC) cells and examined its roles in the proliferation and migration in vitro and in vivo. METHODS: We used the Kaplan-Meier plotter to analyze the survival of different levels of PRDX2 in lung cancer patients. The expression of PRDX2 in normal bronchial epithelial cell line and NSCLC cell lines was measured by qRT-PCR and western blot assays. Biological functions of NSCLC cells were detected by CCK8 and Transwell assays. We constructed tumor growth model using subcutaneously injection of nude mice and metastasis model by tail vein injection in vivo. The protein levels of proliferation related markers were measured by immunohistochemistry assay. Immunofluorescence method was used to detected EMT-related proteins. RESULTS: The high levels of PRDX2 were associated with bad prognosis in lung cancer patients, especially in patients with adenocarcinoma. The expression of PRDX2 in NSCLC cell lines was higher than normal bronchial epithelial cells. Knockdown of PRDX2 inhibited the proliferation, migration, and invasion in A549 cells, while overexpression of PRDX2 promoted the malignancy in NCI-H1299 cells in vitro. Silencing PRDX2 restrained tumor growth and repressed lung metastasis by EMT in vivo. CONCLUSION: Our data indicates that PRDX2 functions as a protumor regulator and is involved in tumorigenesis and tumor progression of lung cancer.

Antioxidant activity of novel imidazo[2,1-b]thiazole derivatives: Design, synthesis, biological evaluation, molecular docking study and in silico ADME prediction.

A series of novel oxo-hydrazone and spirocondensed-thiazolidine derivatives of imidazo[2,1-b]thiazole were synthesized and evaluated for their antioxidant activity. The antioxidant activity of 18 newly synthesized compounds and 12 previously reported compounds bearing similar scaffold, were evaluated by three different methods: inhibition of FeCl3/ascorbate system-induced lipid peroxidation of lecithin liposome (anti-LPO), scavenging activity against ABTS radical and Ferric Reducing Antioxidant Power (FRAP) activity. 4h, 5h, and 6h displayed the highest anti-LPO and ABTS radical removal activity. Also, in FRAP analysis, 4i and 4a displayed the best activity. In addition to the in vitro analysis, docking studies targeting the active site of Human peroxiredoxin 5 (PDB ID: 1HD2) were employed to explore the possible interactions of these compounds with the receptor. Structure-activity relationships, as well as virtual ADME studies, were carried out and a relationship between biological, electronic, and physicochemical qualifications of the target compounds was determined.

Inhibition of the antioxidant enzyme PRDX1 activity promotes MPP+-induced death in differentiated SH-SY5Y cells and may impair its colocalization with eEF1A2.

AIM: eEF1A2 is highly expressed in postmitotic cells and has been reported to interact with the antioxidant enzyme peroxiredoxin 1 (PRDX1). PRDX1 is involved in motor neuron differentiation. Here, we studied the relationship between eEF1A2 and PRDX1 during dopaminergic neuron differentiation, and examined their possible association in an oxidative stress model of Parkinson's disease (PD). MAIN METHODS: Expression of eEF1A2 and PRDX1 in SH-SY5Y cells at various durations of retinoic acid (RA) induction was detected using qRT-PCR, Western blotting and immunofluorescence. Neurons of 10-day differentiation were treated with the PRDX1 inhibitor H7, MPP+ and H7 plus MPP+. The cell viability, the amounts of apoptotic nuclei, DHE signals, and the expression of p53, p-Akt and p-mTOR were determined. The colocalization of eEF1A2 and PRDX1 was visualized using confocal microscopy. KEY FINDINGS: eEF1A2 gradually increased after RA-induced differentiation of SH-SY5Y cells, while PRDX1 protein gradually decreased. MPP+ treatment increased eEF1A2 in both undifferentiated and differentiated neurons; however, PRDX1 appeared to elevate only in mature neurons. The inhibition of the PRDX1 activity with H7 promoted MPP+-induced cell death, as evidenced by decreased cell viability, increased apoptotic nuclei, increased the DHE signal, and increased p53. However, H7 induced the activation of the prosurvival Akt and mTOR in MPP+-treated cells. Besides, a colocalization of eEF1A2 and PRDX1 was evidenced in MPP+-treated neurons. This colocalization was possibly prevented by inhibiting the PRDX1 activity, resulting in aggravated neuronal death. SIGNIFICANCE: Our results suggest that the possible association between eEF1A2 and PRDX1 may be a promising target for modifying neuronal death in PD.

Suppression of PRDX4 inhibits cell proliferation and invasion of ectopic endometrial stromal cells in endometriosis.

Oxidative stress (OS) has been proposed to play a role in the development of EMs. Peroxiredoxins are a family of antioxidant proteins that exhibit peroxidase activity in a thioredoxin-dependent manner, protecting cells against OS. The Western blotting results showed that the relative expression of PRDX4 was significantly increased in ectopic endometria compared with the normal endometria of EMs-free (p < .05). The H2O2 concentration was also significantly higher in the ectopic endometrium. PRDX4 siRNA was transfected into primary ectopic endometrial stromal cells (EESCs). The viability of the transfected EESCs was measured by CCK-8 assay, and the results showed significantly decreased cell viability. Furthermore, the apoptosis rate and ROS generation in flow cytometry assays were significantly increased after the knockdown of PRDX4 expression (p < .05). Scratch assays and transwell assays revealed that decreased expression of PRDX4 mediated by siRNA inhibited EESC migration and invasion. In conclusion, these findings indicate the potential role of PRDX4 in the development of EMs and PRDX4 as a possible therapeutic target for EMs treatment.

Involvement of peroxiredoxin 2 in cumulus expansion and oocyte maturation in mice.

Peroxiredoxin 2 (Prdx2), an antioxidant enzyme, is expressed in the ovary during the ovulatory process. The aim of the present study was to examine the physiological role of Prdx2 during ovulation using Prdx2-knockout mice and mouse cumulus-oocyte complex (COC) from WT mice. Two days of treatment of immature mice (21-23 days old) with equine chorionic gonadotrophin and followed by treatment with human chorionic gonadotrophin greatly impaired cumulus expansion and oocyte maturation in Prdx2-knockout but not wild-type mice. Treatment of COCs in culture with conoidin A (50µM), a 2-cys Prdx inhibitor, abolished epiregulin (EPI)-induced cumulus expansion. Conoidin A treatment also inhibited EPI-stimulated signal molecules, including signal transducer and activator of transcription-3, AKT and mitogen-activated protein kinase 1/2. Conoidin A treatment also reduced the gene expression of EPI-stimulated expansion-inducing factors (hyaluronan synthase 2 (Has2), pentraxin 3 (Ptx3), TNF-α induced protein 6 (Tnfaip6) and prostaglandin-endoperoxide synthase 2 (Ptgs2)) and oocyte-derived factors (growth differentiation factor 9 (Gdf9) and bone morphogenetic protein 15 (Bmp15)). Furthermore, conoidin A inhibited EPI-induced oocyte maturation and the activity of connexins 43 and 37. Together, these results demonstrate that Prdx2 plays a role in regulating cumulus expansion and oocyte maturation during the ovulatory process in mice, probably by modulating epidermal growth factor receptor signalling.

Peroxiredoxin 1 plays a primary role in protecting pancreatic ß-cells from hydrogen peroxide and peroxynitrite.

Both reactive nitrogen and oxygen species (RNS and ROS), such as nitric oxide, peroxynitrite, and hydrogen peroxide, have been implicated as mediators of pancreatic ß-cell damage during the pathogenesis of autoimmune diabetes. While ß-cells are thought to be vulnerable to oxidative damage due to reportedly low levels of antioxidant enzymes, such as catalase and glutathione peroxidase, we have shown that they use thioredoxin reductase to detoxify hydrogen peroxide. Thioredoxin reductase is an enzyme that participates in the peroxiredoxin antioxidant cycle. Peroxiredoxins are expressed in ß-cells and, when overexpressed, protect against oxidative stress, but the endogenous roles of peroxiredoxins in the protection of ß-cells from oxidative damage are unclear. Here, using either glucose oxidase or menadione to continuously deliver hydrogen peroxide, or the combination of dipropylenetriamine NONOate and menadione to continuously deliver peroxynitrite, we tested the hypothesis that ß-cells use peroxiredoxins to detoxify both of these reactive species. Either pharmacological peroxiredoxin inhibition with conoidin A or specific depletion of cytoplasmic peroxiredoxin 1 (Prdx1) using siRNAs sensitizes INS 832/13 cells and rat islets to DNA damage and death induced by hydrogen peroxide or peroxynitrite. Interestingly, depletion of peroxiredoxin 2 (Prdx2) had no effect. Together, these results suggest that ß-cells use cytoplasmic Prdx1 as a primary defense mechanism against both ROS and RNS.

Prx2 (Peroxiredoxin 2) as a Cause of Hydrocephalus After Intraventricular Hemorrhage.

Background and Purpose- Our recent study demonstrated that release of Prx2 (peroxiredoxin 2) from red blood cells (RBCs) is involved in the inflammatory response and brain injury after intracerebral hemorrhage. The current study investigated the role of extracellular Prx2 in hydrocephalus development after experimental intraventricular hemorrhage. Methods- There were 4 parts in this study. First, Sprague-Dawley rats received an intraventricular injection of lysed RBC or saline and were euthanized at 1 hour for Prx2 measurements. Second, rats received an intraventricular injection of Prx2, deactivated Prx2, or saline. Third, lysed RBC was coinjected with conoidin A, a Prx2 inhibitor, or vehicle. Fourth, rats received Prx2 injection and were treated with minocycline or saline (i.p.). The effects of Prx2 and the inhibitors were examined using magnetic resonance imaging assessing ventriculomegaly, histology assessing ventricular wall damage, and immunohistochemistry to assess inflammation, particularly at the choroid plexus. Results- Intraventricular injection of lysed RBC resulted in increased brain Prx2 and hydrocephalus. Intraventricular injection of Prx2 alone caused hydrocephalus, ventricular wall damage, activation of choroid plexus epiplexus cells (macrophages), and an accumulation of neutrophils. Conoidin A attenuated lysed RBC-induced injury. Systemic minocycline treatment reduced the epiplexus cell activation and hydrocephalus induced by Prx2. Conclusions- Prx2 contributed to the intraventricular hemorrhage-induced hydrocephalus, probably by inducing inflammatory responses in choroid plexus and ventricular wall damage.

TXNDC9 regulates oxidative stress-induced androgen receptor signaling to promote prostate cancer progression.

Reactive oxygen species (ROS) and ROS-induced oxidative stress are associated with prostate cancer (PCa) development and castrate-resistant tumor progression. This is in part through the activation of the androgen receptor (AR) signaling. However, the molecular underpinning of ROS to activate AR remains poorly understood. Here, we report that the thioredoxin domain-containing 9 (TXNDC9) is an important regulator of ROS to trigger AR signaling. TXNDC9 expression is upregulated by ROS inducer, and increased TXNDC9 expression in patient tumors is associated with advanced clinical stages. TXNDC9 promotes PCa cell survival and proliferation. It is required for AR protein expression and AR transcriptional activity under oxidative stress conditions. Mechanistically, ROS inducers promote TXNDC9 to dissociate from PRDX1, but enhance a protein association with MDM2. Concurrently, PRDX1 enhances its association with AR. These protein interaction exchanges result in not only MDM2 protein degradation, but also PRDX1 mediated AR protein stabilization, and subsequent elevation of AR signaling. Blocking PRDX1 by its inhibitor, Conoidin A (CoA), suppresses AR signaling, PCa cell proliferation, and xenograft tumor growth even under androgen-deprived conditions. These tumor-suppressive effects of CoA were further strengthened when in combination with enzalutamide treatment. Together, these studies demonstrate that the TXNDC9-PRDX1 axis plays an important role for ROS to activate AR functions. It provides a proof-of-principle that co-targeting AR and PRDX1 may be more effective to control PCa growth.

Pentagamavunon-1 (PGV-1) inhibits ROS metabolic enzymes and suppresses tumor cell growth by inducing M phase (prometaphase) arrest and cell senescence.

We previously showed that curcumin, a phytopolyphenol found in turmeric (Curcuma longa), targets a series of enzymes in the ROS metabolic pathway, induces irreversible growth arrest, and causes apoptosis. In this study, we tested Pentagamavunon-1 (PGV-1), a molecule related to curcumin, for its inhibitory activity on tumor cells in vitro and in vivo. PGV-1 exhibited 60 times lower GI50 compared to that of curcumin in K562 cells, and inhibited the proliferation of cell lines derived from leukemia, breast adenocarcinoma, cervical cancer, uterine cancer, and pancreatic cancer. The inhibition of growth by PGV-1 remained after its removal from the medium, which suggests that PGV-1 irreversibly prevents proliferation. PGV-1 specifically induced prometaphase arrest in the M phase of the cell cycle, and efficiently induced cell senescence and cell death by increasing intracellular ROS levels through inhibition of ROS-metabolic enzymes. In a xenograft mouse model, PGV-1 had marked anti-tumor activity with little side effects by oral administration, whereas curcumin rarely inhibited tumor formation by this administration. Therefore, PGV-1 is a potential therapeutic to induce tumor cell apoptosis with few side effects and low risk of relapse.

Exploring the Natural Piericidins as Anti-Renal Cell Carcinoma Agents Targeting Peroxiredoxin 1.

Anti-renal cell carcinoma (RCC) agents with new mechanisms of action are urgently needed. Twenty-seven natural products of the piericidin class, including 17 new ones, are obtained from a marine-derived Streptomyces strain, and several of them show strong inhibitory activities against ACHN renal carcinoma cells. By exploring the mechanisms of two representative natural piericidin compounds, piericidin A (PA) and glucopiericidin A (GPA), peroxiredoxin 1 (PRDX1) is detected as a potential target by transcriptome data of PA-treated ACHN cells, as well as the paired RCC tumor versus adjacent nontumor tissues. PA and GPA induce cell apoptosis through reducing the reactive oxygen species level caused by upregulated PRDX1 mRNA and protein level subsequently and exhibit potent antitumor efficacy in nude mice bearing ACHN xenografts, with increasing PRDX1 expression in tumor. The interaction between PA/GPA and PRDX1 was supported by the docking analysis and surface plasmon resonance. Moreover, the translocation of PRDX1 into the nucleus forced by PA/GPA is proposed to be a key factor for the anti-RCC procedure. Piericidins provide a novel scaffold for further development of potent anti-RCC agents, and the new action mechanism of these agents targeting PRDX1 may improve upon the limitations of existing targeted drugs for the treatment of renal cancer.

Small interfering RNA targeting of peroxiredoxinâ ¡ gene enhances formaldehyde-induced toxicity in bone marrow cells isolated from BALB/c mice.

BACKGROUDS: Formaldehyde (FA) is an important chemicals that can induce sick house syndrome and may be an incentive of childhood leukemia, however the exact mechanism is unclear. Oxidative stress may be an underlying reason of cancer occurring, while diverse antioxidants can protect the bone marrow cells (BMCs) from damaged. PeroxiredoxinⅡ (PrxⅡ) is an important member of the peroxiredoxin family, can remove reactive oxygen species (ROS), and is closely related with the occurrence of tumor. The present study aimed to detect a possible relationship between PrxⅡ gene and FA-induced bone marrow toxicity. METHODS: The BMCs were taken out from BALB/c mice, then exposed to control and different doses of FA (50, 100, 200 µmol/L). The cell viability, ROS level and expressions of PrxⅡ gene were examined. Afterwards, we used a small interfering RNA (siRNA) to inhibit the expression of PrxⅡ gene, and chose 100 µmol/L FA for exposure dose, to examine the cell viability, ROS level, cell cycle, apoptotic rate, expressions of PrxⅡ gene in BMCs. RESULTS: After a 24 h exposure to different doses of FA, the cell viability, expressions of PrxⅡ gene were decreased with the increasing of FA concentration, while the ROS level was increased. Inhibiting PrxⅡ gene's expression could enhance above FA-induced events. Additionally, siRNA targeting of PrxⅡcould aggravate cell cycle arrest to inhibit cell's growth and development, as well as increase apoptotic rates induced by FA. CONCLUSION: These results demonstrated that PrxⅡ gene was involved in FA-induced bone marrow toxicity, and siRNA targeting of PrxⅡcould enhance this toxic process.

Parvifoline AA Promotes Susceptibility of Hepatocarcinoma to Natural Killer Cell-Mediated Cytolysis by Targeting Peroxiredoxin.

Natural killer (NK) cells play a crucial role in the surveillance of malignant cells. The engagement of NK group 2 member D (NKG2D) receptor with its ligands on target cells represents a promising therapeutic strategy against cancers. Here, we report that parvifoline AA (PAA), a natural ent-kaurane diterpenoid, markedly stimulates the expression of NKG2D ligands on hepatocellular carcinoma (HCC) cells, considerably enhancing their recognition and lysis by NK cells. We determined that PAA covalently binds to the conserved cysteine site of peroxiredoxins I/II (Prxs-I/II) and inhibits their catalytic activity, subsequently activating the ROS/ERK axis and the immunogenicity of HCC toward NK cells. Robust tumor growth inhibition by PAA dependent on NK cell activation was detected in vivo. Our data suggest Prxs-I/II as a promising cancer immune therapeutic target and provide a compelling rationale for further development of the inhibitor PAA as a sensitizer agent for NK cell-mediated HCC immunotherapy.