ABSTRACT
Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.
Subject(s)
Cellular Senescence , Liver Neoplasms , Telomere Shortening , Telomeric Repeat Binding Protein 2 , Telomeric Repeat Binding Protein 2/metabolism , Telomeric Repeat Binding Protein 2/antagonists & inhibitors , Telomeric Repeat Binding Protein 2/genetics , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Animals , Telomere Shortening/drug effects , Cellular Senescence/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Mice , Mice, Nude , Cell Proliferation/drug effects , Mice, Inbred BALB C , Male , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Chinese herbal medicine (CHM) has been widely used in the treatment of hemorrhagic shock (HS) in China. Many controlled trials have been undertaken to investigate its efficacy. OBJECTIVE: To evaluate the effectiveness and safety of CHM for Hemorrhagic Shock patients. METHODS: We screening the Web of ScienceDirect database, PubMed, the Cochrane Library, EMBASE, China Biomedical Database web (CBM), China National Knowledge Infrastructure (CNKI) and WanFang database (WF), from inception to January 2015. All the randomized controlled trials (RCTs) that compared CHM plus conventional therapy with conventional therapy alone for HS patients were included. Meta-analysis on included studies was performed using fixed-effects model with RevMan 5.2. Risk ratio (RR) or mean difference (MD) with a 95% confidence interval (CI) was used as effect measure. STATA 12.0 was used for publication bias. RESULTS: Fifteen RCTs involving 1076 participants were included in the meta-analysis. CHM combined with conventional therapy was tested to be more effective in reduce mortality (RR=0.24, 95%CI:0.13-0.46, P<0.0001), reduce the incidence of MODS (RR=0.47, 95%CI: 0.34-0.66,P<0.00001), symptomatic improvement: increase blood pressure (BP) (MD=8.83, 95%CI:6.82-10.84,P<0.00001), regulate heart rate (MD=-7.6,95%CI:-9.17 to -6.02,P<0.00001), increase urine volume (MD=7.26, 95%CI:5.00-9.53, P<0.00001), compared with conventional therapy alone. No serious adverse events were reported. CONCLUSIONS: CHM combined with conventional therapy seems to be more effective on HS patients. However, the analysis results should be interpreted with caution due to the low methodological quality of the included trials. Future, the rigorously designed, high methodological quality, multicenter and large-scale trials are needed to confirm these conclusions.