ABSTRACT
Oncolytic adenovirus therapy is gaining importance as a novel treatment option for the management of various cancers. Different concepts of modification within the adenovirus vector have been identified that define the mode of action against and the interaction with the tumour. Adenoviral vectors allow for genetic manipulations that restrict tumour specificity and also the expression of specific transgenes in order to support the anti-tumour effect. Additionally, replication of the virus and reinfection of neighbouring tumour cells amplify the therapeutic effect. Another important aspect in oncolytic adenovirus therapy is the virus induced cell death which is a process that activates the immune system against the tumour. This review describes which elements in adenovirus vectors have been identified for modification not only to utilize oncolytic adenovirus vectors into conditionally replicating adenoviruses (CRAds) that allow replication specifically in tumour cells but also to confer specific characteristics to these viruses. These advances in development resulted in clinical trials that are summarized based on the conceptual design.
Subject(s)
Adenoviridae/genetics , Genetic Vectors/genetics , Neoplasms/therapy , Oncolytic Virotherapy/methods , Oncolytic Viruses/genetics , Adenoviridae/immunology , Animals , Clinical Trials as Topic/methods , Clinical Trials as Topic/statistics & numerical data , Genetic Vectors/immunology , Humans , Neoplasms/genetics , Neoplasms/immunology , Oncolytic Viruses/immunology , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Virus Replication/genetics , Virus Replication/immunologyABSTRACT
The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Oncolytic Virotherapy/methods , Protein Kinase Inhibitors/pharmacology , STAT3 Transcription Factor/antagonists & inhibitors , STAT6 Transcription Factor/antagonists & inhibitors , Urinary Bladder Neoplasms/therapy , Animals , Apoptosis/drug effects , Cell Line, Tumor , Chick Embryo , Combined Modality Therapy/methods , Cyclic S-Oxides/pharmacology , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Humans , Hydroxybenzoates/pharmacology , Janus Kinases/antagonists & inhibitors , Nitriles , Nitrofurans/pharmacology , Pyrazoles/pharmacology , Pyrimidines , Quinoxalines/pharmacology , Urinary Bladder Neoplasms/metabolismABSTRACT
Glucose-regulated protein 78 [GRP78, also termed binding immunoglobulin heavy chain protein (Bip)] may be involved in cancer progression and metastasis. However, to date there has been minimal investigation into its potential role in human prostate cancer cells. Recent studies have demonstrated that asymmetric small interfering RNA (asiRNA)-mediated gene silencing is more effective and longer-lasting than conventional symmetric siRNA. Thus, the current study aimed to investigate the effects of GRP78-specific asiRNA on human prostate cancer cells. A series of asiRNAs was synthesized and their efficiency in silencing GRP78 expression in PC-3 human prostate cancer cells was evaluated. The effects of knockdown using asiRNAs were compared to those of knockdown using symmetric siRNAs. The effect of GRP78 silencing on PC-3 cell apoptosis and migration, and the possible mechanisms governing these biological processes were examined. Compared with the symmetric siRNA, transfection with the 15 base pair asiRNA (asiGRP78-3) resulted in greater downregulation of GRP78 expression. GRP78 depletion in PC-3 cells resulted in increased apoptosis and decreased migration of these cells. Experiments investigating the underlying mechanisms of these effects revealed that knockdown of GRP78 attenuated protein kinase B activation and decreased the expression of pro-caspase 9, pro-caspase 3 and vimentin. In conclusion, knockdown of GRP78/Bip expression with asymmetric siRNA led to increased prostate cancer cell apoptosis and reduced cellular migration.
