Been proposed that the loss of p53 function in cancer cells

Been proposed that the loss of p53 function in cancer cells is associated with their ability to avoid apoptosis [146]. Mutations of p53 are involved in resistance to chemotherapy [147]. It was demonstrated that p53 regulated Nrf2 negatively and interfered with the ability of Nrf2 to bind to DNA. A low level of p53 favoured binding of Nrf2 to DNA. In a recent study, the treatment with bortezomib, which is a selective proteasome inhibitor, induced Myelocytomatosis Viral Oncogene Neuroblastoma (MYCN) downregulated p53 expression, leading to cell survival in neuroblastoma [148]. 3.4.2. Bcl-2 Antiapoptotic Protein. Bcl-2 protein is a member of a family of apoptosis-modulating proteins which protects against a variety of apoptotic stimuli, mainly acting at the LOR-253 site mitochondrial level. In addition to its antiapoptotic action, Bcl-2 has been shown to exert potent antioxidant effects [149] such as protection of lipid membranes against peroxidation reactions, maintenance of cellular redox status (i.e., NADH/NAD+ and GSH/GSSG in a reduced state) in response to oxidative stress [150], and elevation of cellular levels of glutathione and reducing equivalents [151]. Bcl-2 upregulates antioxidant defence systems, and its mitochondrial localisation contributes to achieving this effect. Bcl-2 is capable of forming ion channels as a regulator of mitochondrial permeability transition [152]. Mitochondrial permeability transition blockade prevents release of cytochrome c, an apoptosis initiating factor. Herrmann et al. reported that Bcl2 selectively regulates nuclear localisation of cell death regulators such as p53 and NF-B [153]. Cellular redox state via thiols plays a major role in regulating mitochondria-mediated events during apoptosis, and oxidation of mitochondrial thiols is an apoptotic sensor. GSH is involved in detoxifying9 reactions and it has a high intracellular concentration. It serves as the major reducing peptide within all of the cells, due to its sulfhydryl group buffering and removing free radicals generated during metabolic processes such as respiration. GSH is an important BLU-554 cost factor for Bcl-2 ability to suppress apoptosis. Chaiswing et al. observed that thiol redox status and activities and expression of several antioxidant enzymes exhibited distinct patterns in two prostate cancer cell lines at different growth phases, suggesting that modulation of thiol redox status might be useful as a therapeutic tool to modify cancer cell proliferation and tumour aggressiveness [154]. Mitochondrial metabolism is altered in malignant cells so that, in contrast to normal or benign cells, malignant cells accumulate citrate due to low activity of mitochondrial aconitase, become citrate-oxidising cells, and exhibit low amounts of citrate. The higher rate of mitochondrial substrate metabolism explains the increased levels of ROS associated with malignancy and metastasis. The foregoing discussion illustrates the importance of GSH in mitochondrial function and redox status, in determining the metastatic aggressiveness and sensitivity of cancer cells to chemotherapeutic agents, and provides the rationale for mitochondrial GSH as a potential therapeutic target in cancer [155]. 3.5. Chemotherapy-Induced Transcription and Activity of Aromatic Hydrocarbons (Ah) Receptor. AhR is a basic helix-loophelix transcription factor that, prior to ligand binding, is stabilised in the cytoplasm by direct interaction with several proteins such as heat shock protein 90, its cochape.Been proposed that the loss of p53 function in cancer cells is associated with their ability to avoid apoptosis [146]. Mutations of p53 are involved in resistance to chemotherapy [147]. It was demonstrated that p53 regulated Nrf2 negatively and interfered with the ability of Nrf2 to bind to DNA. A low level of p53 favoured binding of Nrf2 to DNA. In a recent study, the treatment with bortezomib, which is a selective proteasome inhibitor, induced Myelocytomatosis Viral Oncogene Neuroblastoma (MYCN) downregulated p53 expression, leading to cell survival in neuroblastoma [148]. 3.4.2. Bcl-2 Antiapoptotic Protein. Bcl-2 protein is a member of a family of apoptosis-modulating proteins which protects against a variety of apoptotic stimuli, mainly acting at the mitochondrial level. In addition to its antiapoptotic action, Bcl-2 has been shown to exert potent antioxidant effects [149] such as protection of lipid membranes against peroxidation reactions, maintenance of cellular redox status (i.e., NADH/NAD+ and GSH/GSSG in a reduced state) in response to oxidative stress [150], and elevation of cellular levels of glutathione and reducing equivalents [151]. Bcl-2 upregulates antioxidant defence systems, and its mitochondrial localisation contributes to achieving this effect. Bcl-2 is capable of forming ion channels as a regulator of mitochondrial permeability transition [152]. Mitochondrial permeability transition blockade prevents release of cytochrome c, an apoptosis initiating factor. Herrmann et al. reported that Bcl2 selectively regulates nuclear localisation of cell death regulators such as p53 and NF-B [153]. Cellular redox state via thiols plays a major role in regulating mitochondria-mediated events during apoptosis, and oxidation of mitochondrial thiols is an apoptotic sensor. GSH is involved in detoxifying9 reactions and it has a high intracellular concentration. It serves as the major reducing peptide within all of the cells, due to its sulfhydryl group buffering and removing free radicals generated during metabolic processes such as respiration. GSH is an important factor for Bcl-2 ability to suppress apoptosis. Chaiswing et al. observed that thiol redox status and activities and expression of several antioxidant enzymes exhibited distinct patterns in two prostate cancer cell lines at different growth phases, suggesting that modulation of thiol redox status might be useful as a therapeutic tool to modify cancer cell proliferation and tumour aggressiveness [154]. Mitochondrial metabolism is altered in malignant cells so that, in contrast to normal or benign cells, malignant cells accumulate citrate due to low activity of mitochondrial aconitase, become citrate-oxidising cells, and exhibit low amounts of citrate. The higher rate of mitochondrial substrate metabolism explains the increased levels of ROS associated with malignancy and metastasis. The foregoing discussion illustrates the importance of GSH in mitochondrial function and redox status, in determining the metastatic aggressiveness and sensitivity of cancer cells to chemotherapeutic agents, and provides the rationale for mitochondrial GSH as a potential therapeutic target in cancer [155]. 3.5. Chemotherapy-Induced Transcription and Activity of Aromatic Hydrocarbons (Ah) Receptor. AhR is a basic helix-loophelix transcription factor that, prior to ligand binding, is stabilised in the cytoplasm by direct interaction with several proteins such as heat shock protein 90, its cochape.