ABSTRACT
Evidence indicates that hypoxia and oxidative stress can control metabolic reprogramming of cancer cells and other cells in tumor microenvironments and that the reprogrammed metabolic pathways in cancer tissue can also alter the redox balance. Thus, important steps toward developing novel cancer therapy approaches would be to identify and modulate critical biochemical nodes that are deregulated in cancer metabolism and determine if the therapeutic efficiency can be influenced by changes in redox homeostasis in cancer tissues. In this review, we will explore the molecular mechanisms responsible for the metabolic reprogramming of tumor microenvironments, the functional modulation of which may disrupt the effects of or may be disrupted by redox homeostasis modulating cancer therapy.
Subject(s)
Hypoxia , Homeostasis , Metabolic Networks and Pathways , Metabolism , Oxidation-Reduction , Oxidative Stress , Tumor MicroenvironmentABSTRACT
Butylated hydroxyanisole (BHA) is a synthetic phenolic compound consisting of a mixture of two isomeric organic compounds: 2-tert-butyl-4-hydroxyanisole and 3-tert-butyl-4-hydroxyanisole. We examined the effect of BHA against hydrogen peroxide (H2O2)-induced apoptosis in primary cultured mouse hepatocytes. Cell viability was significantly decreased by H2O2 in a dose-dependent manner. Additionally, H2O2 treatment increased Bax, decreased Bcl-2, and promoted PARP-1 cleavage in a dose-dependent manner. Pretreatment with BHA before exposure to H2O2 significantly attenuated the H2O2-induced decrease of cell viability. H2O2 exposure resulted in an increase of intracellular reactive oxygen species (ROS) generation that was significantly inhibited by pretreatment with BHA or N-acetyl-cysteine (NAC, an ROS scavenger). H2O2-induced decrease of cell viability was also attenuated by pretreatment with BHA and NAC. Furthermore, H2O2-induced increase of Bax, decrease of Bcl-2, and PARP-1 cleavage was also inhibited by BHA. Taken together, results of this investigation demonstrated that BHA protects primary cultured mouse hepatocytes against H2O2-induced apoptosis by inhibiting ROS generation.
Subject(s)
Animals , Male , Mice , Apoptosis/drug effects , Butylated Hydroxyanisole/chemistry , Cell Survival/drug effects , Cells, Cultured , Hepatocytes/drug effects , Hydrogen Peroxide/toxicity , Mice, Inbred ICR , Molecular StructureABSTRACT
Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2-33.7 muM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF-525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds.
Subject(s)
Humans , Cytochrome P-450 CYP1A2 , Cytochrome P-450 CYP2D6 , Cytochrome P-450 CYP2E1 , Cytochrome P-450 Enzyme System , Hydrolysis , Metabolism , Microsomes, Liver , Proadifen , Protein IsoformsABSTRACT
Adhesion and migration of vascular smooth muscle cells (VSMCs) play an important role in the pathogenesis of atherosclerosis. These processes involve the interaction of VSMCs with extracellular matrix proteins. Here, we investigated integrin isoforms and signaling pathways mediating the adhesion and migration of VSMCs on betaig-h3, a transforming growth factor (TGF)-beta-inducible extracellular matrix protein that is elevated in atherosclerotic plaques. Adhesion assays showed that the alphavbeta5 integrin is a functional receptor for the adhesion of aortic VSMCs to betaig-h3. An YH18 motif containing amino acids between 563 and 580 of betaig-h3 was an essential motif for the adhesion and growth of VSMCs. Interaction between the YH18 motif and the alphavbeta5 integrin was responsible for the migration of VSMCs on betaig-h3. Inhibitors of phosphatidylinositide 3-kinase, extracellular signal-regulated kinase (ERK), and Src kinase reduced the adhesion and migration of VSMCs on betaig-h3. betaig-h3 triggered phosphorylation and activation of AKT, ERK, focal adhesion kinase, and paxillin mediating the adhesion and migration of VSMCs. Taken together, these results suggest that betaig-h3 and alphavbeta5 integrin play a role in the adhesion and migration of VSMCs during the pathogenesis of atherosclerosis.
Subject(s)
Humans , Animals , src-Family Kinases/antagonists & inhibitors , Transforming Growth Factor beta/genetics , Signal Transduction/physiology , Receptors, Vitronectin/genetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Paxillin/metabolism , Myocytes, Smooth Muscle/drug effects , Muscle, Smooth, Vascular/cytology , Morpholines/pharmacology , Molecular Sequence Data , Integrins/genetics , Flavonoids/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Matrix Proteins/genetics , Enzyme Inhibitors/pharmacology , Chromones/pharmacology , Cells, Cultured , Cell Movement/physiology , Cell Adhesion/physiology , Amino Acid Sequence , Amino Acid Motifs/genetics , Phosphatidylinositol 3-Kinase/antagonists & inhibitorsABSTRACT
Betaig-h3 (betaig-h3) is a secretory protein composed of fasciclin I-like repeats containing sequences that allows binding of integrins and glycosaminoglycans in vivo. Expression of betaig-h3 is responsive to TGF-beta and the protein is found to be associated with extracellular matrix (ECM) molecules, implicating betaig-h3 as an ECM adhesive protein of developmental processes. We previously observed predominant expression of betaig-h3 expression in the basement membrane of proximal tubules of kidney. In this study, the physiological relevance of such localized expression of betaig-h3 was examined in the renal proximal tubular epithelial cells (RPTEC). RPTEC constitutively expressed betaig-h3 and the expression was dramatically induced by exogenous TGF-beta1 treatment. betaig-h3 and its second and fourth FAS1 domain were able to mediate RPTEC adhesion, spreading and migration. Two known alpha3beta1 integrin-interaction motifs including aspartatic acid and isoleucine residues, NKDIL and EPDIM in betaig-h3 were responsible to mediate RPTEC adhesion, spreading, and migration. By using specific antibodies against integrins, we confirmed that alpha3beta1 integrin mediates the adhesion and migration of RPTECs on betaig-h3. In addition, it also enhanced proliferation of RPTECs through NKDIL and EPDIM. These results indicate that betaig-h3 mediates adhesion, spreading, migration and proliferation of RPTECs through the interaction with alpha3beta1 integrin and is intimately involved in the maintenance and the regeneration of renal proximal tubular epithelium.