73 research outputs found
Anti-vascular agent Combretastatin A-4-P modulates Hypoxia Inducible Factor-1 and gene expression
No full textBackground
A functional vascular network is essential for the survival, growth and spread of solid tumours, making blood vessels a key target for therapeutic strategies. Combretastatin A-4 phosphate (CA-4-P) is a tubulin-depolymerising agent in Phase II clinical trials as a vascular disrupting agent. Not much is known of the molecular effect of CA-4-P under tumour conditions. The tumour microenvironment differs markedly from that in normal tissue, specifically with respect to oxygenation (hypoxia). Gene regulation under tumour conditions is governed by hypoxia inducible factor 1 (HIF-1), controlling angiogenic and metastatic pathways.
Methods
We investigated the effect of CA-4-P on factors of the upstream and downstream signalling pathway of HIF-1 in vitro.
Results
CA-4-P treatment under hypoxia tended to reduce HIF-1 accumulation in a concentration-dependent manner, an effect which was more prominent in endothelial cells than in cancer cell lines. Conversely, CA-4-P increased HIF-1 accumulation under aerobic conditions in vitro. At these concentrations of CA-4-P under aerobic conditions, nuclear factor κB was activated via the small GTPase RhoA, and expression of the HIF-1 downstream angiogenic effector gene, vascular endothelial growth factor (VEGF-A), was increased.
Conclusion
Our findings advance the understanding of signal transduction pathways involved in the actions of the anti-vascular agent CA-4-P
Cellular Effects and Signalling Pathways Activated by the Anti-Coagulant Factor, Protein S, in Vascular Cells
No full textTumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics
No full textVascular endothelial growth factor-A (VEGF) is produced by most cancer cells as multiple isoforms, which display distinct biological activities. VEGF plays an undisputed role in tumour growth, vascularisation and metastasis; nevertheless the functions of individual isoforms in these processes remain poorly understood. We investigated the effects of three main murine isoforms (VEGF188, 164 and 120) on tumour cell behaviour, using a panel of fibrosarcoma cells we developed that express them individually under endogenous promoter control. Fibrosarcomas expressing only VEGF188 (fs188) or wild type controls (fswt) were typically mesenchymal, formed ruffles and displayed strong matrix-binding activity. VEGF164- and VEGF120-producing cells (fs164 and fs120 respectively) were less typically mesenchymal, lacked ruffles but formed abundant cell-cell contacts. On 3D collagen, fs188 cells remained mesenchymal while fs164 and fs120 cells adopted rounded/amoeboid and a mix of rounded and elongated morphologies respectively. Consistent with their mesenchymal characteristics, fs188 cells migrated significantly faster than fs164 or fs120 cells on 2D surfaces while contractility inhibitors accelerated fs164 and fs120 cell migration. VEGF164/VEGF120 expression correlated with faster proliferation rates and lower levels of spontaneous apoptosis than VEGF188 expression. Nevertheless, VEGF188 was associated with constitutively active/phosphorylated AKT, ERK1/2 and Stat3 proteins. Differences in proliferation rates and apoptosis could be explained by defective signalling downstream of pAKT to FOXO and GSK3 in fs188 and fswt cells, which also correlated with p27/p21 cyclin-dependent kinase inhibitor over-expression. All cells expressed tyrosine kinase VEGF receptors, but these were not active/activatable suggesting that inherent differences between the cell lines are governed by endogenous VEGF isoform expression through complex interactions that are independent of tyrosine kinase receptor activation. VEGF isoforms are emerging as potential biomarkers for anti-VEGF therapies. Our results reveal novel roles of individual isoforms associated with cancer growth and metastasis and highlight the importance of understanding their diverse actions
Wearable Insulin Biosensors for Diabetes Management: Advances and Challenges
No full textWe present a critical review of the current progress in wearable insulin biosensors. For over 40 years, glucose biosensors have been used for diabetes management. Measurement of blood glucose is an indirect method for calculating the insulin administration dosage, which is critical for insulin-dependent diabetic patients. Research and development efforts aiming towards continuous-insulin-monitoring biosensors in combination with existing glucose biosensors are expected to offer a more accurate estimation of insulin sensitivity, regulate insulin dosage and facilitate progress towards development of a reliable artificial pancreas, as an ultimate goal in diabetes management and personalised medicine. Conventional laboratory analytical techniques for insulin detection are expensive and time-consuming and lack a real-time monitoring capability. On the other hand, biosensors offer point-of-care testing, continuous monitoring, miniaturisation, high specificity and sensitivity, rapid response time, ease of use and low costs. Current research, future developments and challenges in insulin biosensor technology are reviewed and assessed. Different insulin biosensor categories such as aptamer-based, molecularly imprinted polymer (MIP)-based, label-free and other types are presented among the latest developments in the field. This multidisciplinary field requires engagement between scientists, engineers, clinicians and industry for addressing the challenges for a commercial, reliable, real-time-monitoring wearable insulin biosensor
Microtubule depolymerizing vascular disrupting agents: novel therapeutic agents for oncology and other pathologies
No full text
Rational Design of Cholesterol Derivative for Improved Stability of Paclitaxel Cationic Liposomes
No full text
- …
