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Tumourigenic tissue uses modified metabolic signalling pathways in order to support hyperproliferation and survival. Cancer-associated aerobic glycolysis resulting in lactic acid production was described nearly 100 years ago. Furthermore, increased reactive oxygen species (ROS) and lactate quantities increase metabolic, survival and proliferation signalling, resulting in increased tumourigenesis. In order to maintain redox balance, the cell possesses innate antioxidant defence systems such as superoxide dismutase, catalase and glutathione. Several stimuli including cells deprived of nutrients or failure of antioxidant systems result in oxidative stress and cell death induction. Among the cell death machinery is autophagy, a compensatory mechanism whereby energy is produced from damaged and/or redundant organelles and proteins, which prevents the accumulation of waste products, thereby maintaining homeostasis. Furthermore, autophagy is maintained by several pathways including phosphoinositol 3 kinases, the mitogen-activated protein kinase family, hypoxia-inducible factor, avian myelocytomatosis viral oncogene homolog and protein kinase receptor-like endoplasmic reticulum kinase. The persistent potential of cancer metabolism, redox regulation and the crosstalk with autophagy in scientific investigation pertains to its ability to uncover essential aspects of tumourigenic transformation. This may result in clinical translational possibilities to exploit tumourigenic oxidative status and autophagy to advance our capabilities to diagnose, monitor and treat cancer.
Background: The majority of novel chemotherapeutics target the cell cycle, aiming to effect arrest and cause apoptosis. One such agent, 2-methoxyestradiol (2ME), has been shown to possess anticancer properties against numerous cancer types, both in vitro and in vivo. Despite its promise, 2ME has exhibited limitations, including low oral bioavailability and rapid hepatic enzymatic inactivation in vivo. A novel sulphamoylated estrogen analog, 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16), was in silico-designed in our laboratory to overcome these issues. It was then synthesized by a pharmaceutical company and used in an in vitro antiproliferative effect study on a human cervical carcinoma (HeLa) cell line. Results: Cell proliferation data obtained from the crystal violet assay and realtime cell analysis demonstrated that 0.2 μM of ESE-16 had a significant inhibitory effect on the HeLa cells 24 h post-exposure. Immunofluorescence showed that ESE-16 is a microtubule disruptor that causes cells to undergo a mitotic block. Qualitative morphological studies using polarization-optical transmitted light differential interference contrast (PlasDIC) and light microscopy revealed a decrease in cell density and an increase in the number of cells arrested in metaphase. After ESE-16 exposure, hallmarks of apoptosis were also observed, including membrane blebbing, chromatin condensation and the presence of apoptotic bodies. Flow cytometry provided quantitative results from cell cycle progression analysis, indicating cells undergoing apoptosis and cells in the G2/M phase of the cell cycle, confirming cell cycle arrest in metaphase after ESE-16 treatment. Quantification of the ESE-16-mediated upregulation of cyclin B in HeLa cells and spectrophotometric and flow cytometric confirmation of cell death via apoptosis further confirmed the substance’s impact. Conclusion: ESE-16 exerts its antiproliferative effects through microtubule disruption, which induces a mitotic block culminating in apoptosis. This research provided information on ESE-16 as a potential antitumor agent and on cellular targets that could aid in the design of prospective microtubule-disrupting compounds. Further in vitro and in vivo investigations of this novel compound are needed.
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