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  • mycophenolic acid  (3)
  • 1
    Keywords: EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; human ; IN-VIVO ; VITRO ; VIVO ; microarray ; PROTEIN ; PROTEINS ; RNA ; DRUG ; SURGERY ; PATIENT ; REDUCTION ; TRANSPLANTATION ; RAT ; CONTRAST ; mechanisms ; SKIN ; fibroblasts ; ACID ; PCR ; NUCLEOTIDES ; EXTRACELLULAR-MATRIX ; ADHESION ; MIGRATION ; cytoskeleton ; POLYMERASE-CHAIN-REACTION ; SMOOTH-MUSCLE ; COMPLICATIONS ; BIOPSY ; CHAIN ; fibroblast ; DEHYDROGENASE ; RECIPIENTS ; HUMAN FIBROBLASTS ; cell adhesion ; mycophenolic acid ; TECHNOLOGY ; B-LYMPHOCYTES ; ENGLAND ; ACTIN ; DYSFUNCTION ; synthesis ; NUCLEOTIDE ; CYCLOSPORINE ; MOFETIL ; KIDNEY-TRANSPLANT
    Abstract: Mycophenolic acid (MPA) is a potent inhibitor of the inosine monophosphate dehydrogenase and used as an immunosuppressive drug in transplantation. MPA inhibits proliferation of T- and B-lymphocytes by guanosine depletion. Since fibroblasts rely on the de novo synthesis of guanosine nucleotides, it is assumed that MPA interacts with fibroblasts causing an increased frequency of wound healing problems. We show a downregulation of the cytoskeletal proteins vinculin, actin and tubulin in fibroblasts exposed to pharmacological doses of MPA using microarray technology, real-time polymerase chain reaction (PCR) and Western blot. This reduction in RNA and protein content is accompanied by a substantial rearrangement of the cytoskeleton in MPA-treated fibroblasts as documented by immunofluorescence. The dysfunctional fibroblast growth was validated by scratch test documenting impaired migrational capacity. In contrast, cell adhesion was increased in MPA-treated fibroblasts. The results of the cultured human fibroblasts were applied to skin biopsies of renal transplant recipients. Skin biopsies of patients treated with MPA expressed less vinculin, actin and tubulin as compared to control biopsies that could explain potential wound healing problems posttransplantation. The perspective of MPA-induced cytoskeletal dysfunction may go beyond wound healing disturbances and may have beneficial effects on (renal) allografts with respect to scarring
    Type of Publication: Journal article published
    PubMed ID: 18786225
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  • 2
    Keywords: SURGERY ; TRANSPLANTATION ; VIVO ; VITRO ; IN-VIVO ; human ; IN-VITRO ; proliferation ; fibroblast ; MIGRATION ; ADHESION ; ACID ; ENGLAND ; mycophenolic acid
    Type of Publication: Meeting abstract published
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  • 3
    Keywords: ANGIOGENESIS ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; GROWTH ; IN-VITRO ; proliferation ; tumor ; CELL ; Germany ; human ; IN-VIVO ; INHIBITION ; tumor growth ; VITRO ; VIVO ; DENSITY ; RISK ; GENE ; PROTEIN ; TUMORS ; MICE ; PATIENT ; MECHANISM ; TRANSCRIPTION FACTOR ; TRANSPLANTATION ; mechanisms ; fibroblasts ; ACID ; MALIGNANCIES ; ASSAY ; NUDE-MICE ; MODULATION ; RELATIVE RISK ; signaling ; AGENT ; molecular ; ONCOLOGY ; MOLECULAR-BASIS ; fibroblast ; TUMOR-GROWTH ; DEHYDROGENASE ; mycophenolic acid ; MOLECULAR-MECHANISMS ; analysis ; ASSAYS ; USA ; cancer research ; PROTEIN-KINASE-A ; GLIOBLASTOMA ; microvascular density ; quantitative ; MOFETIL
    Abstract: The relative risk for the development of malignancies following solid organ transplantation seems to be decreased in patients treated with the immunosuppressive agent mycophenolic acid (MPA). However, the molecular mechanisms of the antineoplastic effects of MPA are not completely understood. Here, we report that human endothelial cells and fibroblasts are highly sensitive to MPA treatment. We found that U87 glioblastoma cells were resistant to MPA treatment in vitro. However U87 tumor growth was markedly inhibited in vivo in BALB/c nude mice, suggesting that MPA exerted its antitumor effects via modulation of the tumor microenvironment. Accordingly, microvascular density and pericyte coverage were markedly reduced in MPA-treated tumors in vivo. Using functional in vitro assays, we showed that MPA potently inhibited endothelial cell and fibroblast proliferation, invasion/migration, and endothelial cell tube formation. To identify the genetic participants governing the antiangiogenic and antifibrotic effects of MPA, we performed genome-wide transcriptional analysis in U87, endothelial and fibroblast cells at 6 and 12 h after MPA treatment. Network analysis revealed a critical role for MYC signaling in endothelial cells treated with MPA. Moreover, we found that the antiangiogenic effects of MPA were organized by coordinated communications between MYC and NDRG1, YY1, HIF1A, HDAC2, CDC2, GSK3B, and PRKACB signaling. The regulation of these "hub nodes" was confirmed by real-time quantitative reverse transcription-PCR and protein analysis. The critical involvement of MYC in the antiangiogenic signaling of MPA was further shown by gene knockdown experiments. Together, these data provide a molecular basis for the antiangiogenic and antifibrotic effects of MPA, which warrants further clinical investigations
    Type of Publication: Journal article published
    PubMed ID: 18566237
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