ABSTRACT
Resveratrol has been proposed to prevent tumor growth and the different steps of carcinogenesis; nevertheless, these biological effects are sometimes discordant between different cell types. Several hypotheses and works have suggested that the metabolism of resveratrol could be at the origin of a different cellular response. We show here, using colorectal tumor cell lines, that the biological effects of RSV result mainly from its carriage by carriers of the superfamily of ABC transporter, i.e., P-gP, MRP, or BCRP. Using cell lines overexpressing these different transporters, we have been able to highlight the importance of P-gP in the response of cells to RSV. These results were confirmed by invalidating the gene coding for P-gP, which restored the sensitivity of colorectal cells resistant to the polyphenol. Subsequently, the status of P-glycoprotein expression is an important element to be taken into consideration in the cytotoxic activity of resveratrol in colorectal cancer cells.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Colorectal Neoplasms/drug therapy , Enzyme Inhibitors/pharmacology , Resveratrol/pharmacology , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP-Binding Cassette Transporters/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Colorectal Neoplasms/metabolism , Drug Resistance, Neoplasm , Enzyme Inhibitors/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Gene Silencing , Humans , Resveratrol/metabolismABSTRACT
Studies have suggested involvement of interleukin 17 (IL-17) in autoimmune diseases, although its effect on B cell biology has not been clearly established. Here we demonstrate that IL-17 alone or in combination with B cell-activating factor controlled the survival and proliferation of human B cells and their differentiation into immunoglobulin-secreting cells. This effect was mediated mainly through the nuclear factor-kappaB-regulated transcription factor Twist-1. In support of the relevance of our observations and the potential involvement of IL-17 in B cell biology, we found that the serum of patients with systemic lupus erythematosus had higher concentrations of IL-17 than did the serum of healthy people and that IL-17 abundance correlated with the disease severity of systemic lupus erythematosus.
Subject(s)
B-Cell Activating Factor/pharmacology , B-Lymphocytes/drug effects , Interleukin-17/blood , Interleukin-17/pharmacology , Lupus Erythematosus, Systemic/blood , Antigens, CD19/metabolism , Apoptosis/drug effects , B-Lymphocytes/cytology , B-Lymphocytes/metabolism , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Synergism , Female , Humans , Immunoblotting , Immunoglobulins/metabolism , Interleukin-17/genetics , Lupus Erythematosus, Systemic/pathology , Male , Minor Histocompatibility Antigens , NF-kappa B/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Twist-Related Protein 1/genetics , Twist-Related Protein 1/metabolismABSTRACT
Bio-guided fractionation of the roots of Paris polyphylla (Trilliaceae), based on inhibition of P-glycoprotein-mediated daunorubicin efflux in K562/R7 cell line, led to isolation and identification of the three saponins 3-O-Rha(1-->2)[Ara(1-->4)]Glc-pennogenine, gracillin and polyphyllin D, and the two ecdysteroids 20-hydroxyecdysone and pinnatasterone. These compounds were tested for multidrug reversion on P-glycoprotein (ABCB1) with both drug-selected and transfected cell lines, and also on Breast Cancer Resistance Protein (BCRP/ABCG2). By contrast to a weak efficiency on BCRP, the three saponins displayed significant effects as inhibitors of P-glycoprotein-mediated drug efflux.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP-Binding Cassette Transporters/antagonists & inhibitors , Daunorubicin/metabolism , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Plant Extracts/pharmacology , Saponins/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Cyclosporine/pharmacology , Diosgenin/analogs & derivatives , Diosgenin/isolation & purification , Diosgenin/pharmacology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Ecdysteroids/isolation & purification , Ecdysteroids/pharmacology , Ecdysterone/isolation & purification , Ecdysterone/pharmacology , Humans , Immunosuppressive Agents/pharmacology , K562 Cells , Leukemia/drug therapy , Leukemia/metabolism , Magnoliopsida/chemistry , Membrane Transport Modulators/pharmacology , Plant Extracts/chemistry , Rhizome , Saponins/isolation & purification , Spirostans/isolation & purification , Spirostans/pharmacology , Steroids/isolation & purification , Steroids/pharmacologyABSTRACT
Twist1 and Twist2 are major regulators of embryogenesis. Twist1 has been shown to favor the metastatic dissemination of cancer cells through its ability to induce an epithelial-mesenchymal transition (EMT). Here, we show that a large fraction of human cancers overexpress Twist1 and/or Twist2. Both proteins override oncogene-induced premature senescence by abrogating key regulators of the p53- and Rb-dependent pathways. Twist1 and Twist2 cooperate with Ras to transform mouse embryonic fibroblasts. Interestingly, in epithelial cells, the oncogenic cooperation between Twist proteins and activated mitogenic oncoproteins, such as Ras or ErbB2, leads to complete EMT. These findings suggest an unanticipated direct link between early escape from failsafe programs and the acquisition of invasive features by cancer cells.
Subject(s)
Cell Transdifferentiation , Cell Transformation, Neoplastic/metabolism , Cellular Senescence , Epithelial Cells/metabolism , Fibroblasts/metabolism , Neoplasms/metabolism , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Twist-Related Protein 1/metabolism , Animals , Cell Line , Cell Transdifferentiation/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Cellular Senescence/genetics , Dogs , Enzyme Activation , Epithelial Cells/enzymology , Epithelial Cells/pathology , Fibroblasts/enzymology , Fibroblasts/pathology , Gene Expression Regulation, Neoplastic , Humans , Mammary Glands, Human/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Nude , Mice, Transgenic , Neoplasm Invasiveness , Neoplasms/enzymology , Neoplasms/genetics , Neoplasms/pathology , Nuclear Proteins/genetics , RNA Interference , Repressor Proteins/genetics , Retinoblastoma Protein/metabolism , Transfection , Transplantation, Heterologous , Tumor Suppressor Protein p53/metabolism , Twist-Related Protein 1/genetics , Up-Regulation , ras Proteins/metabolismABSTRACT
A new series of diterpenes, the jatrophanes euphoscopin M (1), euphoscopin N (2) and euphornin L (3), and the lathyrane euphohelioscopin C (7) were isolated from plants of Euphorbia helioscopia L., together with four other known analogues, euphoscopin C (4), euphornin (5), epieuphoscopin B (6) and euphohelioscopin A (8). The new compound stereostructures were elucidated by NMR analysis and computational data. The resulting isolated diterpenes were found to be potent inhibitors of P-glycoprotein (ABCB1), while showing an absence of significant activity against BCRP (ABCG2), despite the high substrate overlapping of these transporters, thus including them in the third-generation class of specific multidrug transporter modulators.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/chemistry , Diterpenes/chemistry , Animals , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Molecular Structure , NIH 3T3 Cells , StereoisomerismABSTRACT
BACKGROUND: Considerable variability in sensitivity to corticosteroids (CS) has been observed among individuals with regard to both the natural and synthetic compounds. The role of genetic polymorphisms in modulating CS function, and hence in disease susceptibility, has been extensively analyzed. Their impact on therapeutic response still remains to be explored. The role of cytochrome P450 (CYP) 3A4 in corticosteroid metabolism, and that of the glucocorticoid receptor (NR3C1) in regulation of responsive genes, renders CYP3A4 and NR3C1 polymorphisms as potential candidates for pharmacogenetic analysis. AIM: The aim of the study was to analyze the role of these polymorphisms in the outcome of a disease treated with CS drugs. METHODS: Towards this aim we analyzed the CYP3A4-290A/G substitution and three NR3C1 polymorphisms (200G/A, 1220A/G and BclI RFLP) in 222 children with acute lymphoblastic leukemia (ALL) whose treatment protocols, among other components, contained corticosteroid drugs. RESULTS: The analysis of survival probabilities in relation to the indicated genotypes showed only an association between homozygosity for allele G of the NR3C1 BclI RFLP polymorphism and overall survival (univariate and multivariate hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.0, 7.6 and 5.2, 95% CI 1.4, 18.9, respectively). The association reflects a correlation with disease progression and prognosis, and may vary depending on risk of relapse. CONCLUSION: A reduction in survival probability in children with ALL was associated with homozygosity for G allele of the NR3C1BclI RFLP polymorphism, particularly in certain patient subgroups. Further analysis is required to replicate this finding and to understand the mechanism underlying the observed association.