A novel thioredoxin reductase inhibitor inhibits cell growth and induces apoptosis in HL-60 and K562 cells

Human thioredoxin reductase (TrxR) system is associated with cancer cell growth and anti-apoptosis process. Effects of 1,2-bis(1,2-benzisoselenazolone-3(2H)-ketone)ethane (BBSKE),a novel TrxR inhibitor,were investigated on human leu-kemia cell lines HL-60 and K562. BBSKE treatment induced cell growth inhibition and apoptosis in both cell lines. Apoptosis induced by BBSKE is through Bcl-2/Bax and caspase-3 pathways. Ehrlich's ascites carcinoma-bearing mice were used to inves-tigate the anti-tumor effect of BBSKE in vivo. Tumor-bearing mice treated with BBSKE showed an increase of life span with a comparable effect to cyclophosphamide (CTX). These results suggest a potential usage of BBSKE as a therapeutic agent against non-solid tumors.

Detection of a novel panel of 24 genes with high frequencies of mutation in gastric cancer based on next-generation sequencing

BACKGROUND Gastric cancer is a leading cause of cancer-related mortality worldwide.Many somatic mutations have been identified based on next-generation sequencing;they likely play a vital role in cancer treatment selection.However,nextgeneration sequencing has not been widely used to diagnose and treat gastric cancer in the clinic.AIM To test the mutant gene frequency as a guide for molecular diagnosis and personalized therapy in gastric cancer by use of next-generation sequencing.METHODS We constructed a panel of 24 mutant genes to detect somatic nucleotide variations and copy number variations based on a next-generation sequencing technique.Our custom panel included high-mutation frequency cancer driver and tumour suppressor genes.Mutated genes were also analyzed using the cBioPortal database.The clinical annotation of important variant mutation sites was evaluated in the ClinVar database.We searched for candidate drugs for targeted therapy and immunotherapy from the OncoKB database.RESULTS In our study,the top 16 frequently mutated genes were TP53(58%),ERBB2(28%),BRCA2(23%),NF1(19%),PIK3CA(14%),ATR(14%),MSH2(12%),FBXW7(12%),BMPR1A(12%),ERBB3(11%),ATM(9%),FGFR2(8%),MET(8%),PTEN(6%),CHD4(6%),and KRAS(5%).TP53 is a commonly mutated gene in gastric cancer and has a similar frequency to that in the cBioPortal database.33 gastric cancer patients(51.6%)with microsatellite stability and eight patients(12.5%)with microsatellite instability-high were investigated.Enrichment analyses demonstrated that high-frequency mutated genes had transmembrane receptor protein kinase activity.We discovered that BRCA2,PIK3CA,and FGFR2 gene mutations represent promising biomarkers in gastric cancer.CONCLUSION We developed a powerful panel of 24 genes with high frequencies of mutation that could detect common somatic mutations.The observed mutations provide potential targets for the clinical treatment of gastric cancer.

Early chronic obstructive pulmonary disease:A new perspective

Chronic obstructive pulmonary disease(COPD)is a respiratory disease with a high incidence,mortality,and disability rate.Because there are few symptoms in the early stages of COPD,diagnosis and treatment are seriously insufficient.It is necessary to find effective clues for early COPD diagnosis and provide appropriate interventions.Several studies suggest that small airway disease is the earliest stage of COPD because it is correlated with subsequent development of airflow obstruction.However,there are currently no globally accepted criteria for defining early COPD.This study mainly introduced risk factors,definition,diagnosis,and treatment of early COPD from a new perspective.

Ethaselen: a novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis

It has been reported that Ethaselen shows inhibitory effects on thioredoxin reductase（TrxR） activity and human tumor cell growth. In order to find an efficient way to reverse cisplatin resistance, we investigated the reversal effects of Ethaselen on cisplatin resistance in K562/cisplatin（CDDP） cells that were established by pulse-inducing human erythrocyte leukemic cell line K562, which are fivefold more resistant to cisplatin compared to K562 cells. The morphology and growth showed that the adhesion of K562/CDDP further decreased while the cell volume increased. The proliferation of K562/CDDP is strengthened. The antitumor activities in vitro were assessed by MTT（3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide） assay and combination index（CI）, showing the significant synergic effects of cisplatin and Ethaselen. Focusing on apoptosis, a series of comparisons was made between K562 and K562/CDDP. Cisplatin induced higher reactive oxygen species（ROS） generation in K562 and subsequently induced the formation of mitochondrial permeability transition pores（PTPs）. In addition, cisplatin increased the ratio of Bax to Bcl-2 in K562, which can influence the mitochondrial membrane permeability. PTP formation and mitochondrial membrane permeabilization eventually resulted in the release of cytochrome c and activation of the Caspase pathway. However, these effects were not clearly seen in K562/CDDP, which may be the reason for the acquired CDDP resistance. However, Ethaselen can induce a high level of ROS in K562/CDDP by TrxR activity inhibition and increased ratio of Bax to Bcl-2 in K562/CDDP by nuclear factor κB（NF-κB） suppression, which subsequently induces the release of cytochrome c in K562/CDDP. This response is partly responsible for the reversal of the cisplatin resistance in K562/CDDP cells.

Novel thioredoxin reductase inhibitor butaselen inhibits tumorigenesis by down-regulating programmed death-ligand 1 expression

The thioredoxin system plays a role in a variety of physiological functions, including cell growth, differenti- ation, apoptosis, tumorigenesis, and immunity. We previously confirmed that butaselen （BS）, a novel thioredoxin reductase inhibitor, can inhibit the growth of various human cancer cell lines, yet the underlying mechanism remains elusive. In this study, we investigated the anti-tumor effect of BS in vivo through regulating the immune system of KM mice. We found that BS inhibits tumor proliferation by promoting the activation of splenic lymphocytes in mice. BS can elevate the percentage of CD^4-CD8^＋ T lymphocytes and the secretion of downstream cytokines in mice via downregulating the expression of programmed death-ligand 1 （PD-L1） on the tumor cells＇ surface in vivo. Further study in HepG2 and BEL-7402 cells showed that decrease of PD-L1 level after BS treatment was achieved by inhibiting signal transducer and activator of transcription 3 （STAT3） phosphorylation. Taken together, our results suggest that BS has a role in promoting the immune response by reducing PD-L1 expression via the STAT3 pathway, and subsequently suppresses tumorigenesis.

Potential metal-related strategies for prevention and treatment of COVID-19

The coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has posed severe threats to human health,public safety,and the global economy.Metal nutrient elements can directly or indirectly take part in human immune responses,and metal-related drugs have served as antiviral drugs and/or enzyme inhibitors for many years,providing potential solutions to the prevention and treatment of COVID-19.Metal-based drugs are currently under a variety of chemical structures and exhibit wide-range bio activities,demonstrating irreplaceable advantages in pharmacology.This review is an intention to summarize recent progress in the prevention and treatment strategies against COVID-19 from the perspective of metal pharmacology.The current and potential utilization of metal-based drugs is briefly introduced.Specifically,metallohydrogels that have been shown to present superior antiviral activities are stressed in the paper as potential drugs for the treatment of COVID-19.