TNP-470, a potent angiogenesis inhibitor, amplifies human T lymphocyte activation through an induction of nuclear factor-kappaB, nuclear factor-AT, and activation protein-1 transcription factors.
TNP-470, an angiogenesis inhibitor derived from fumagillin, is foreseen as a promising anti-cancer drug. Its effectiveness to restrain tumor growth and its lack of major side effects have been demonstrated in several animal models and have led the drug to reach phase III clinical trials. Beside its antiangiogenesis activities, TNP-470 exhibits several effects on the immune system. We had shown previously that TNP-470 stimulated B lymphocyte proliferation through an action on T cells. In this study, we examined the cellular and molecular modifications induced by TNP-470 in normal human T lymphocytes. Transmission electron microscopic examination of PHA/TNP-470-treated T cells revealed significant morphologic modifications when compared with PHA-treated control T cells. TNP-470 induced indeed an important and significant increase of the nuclear size as well as major nuclear chromatin decondensation. This observation indicated that TNP-470 amplified T-cell activation and led us to investigate its effects on the activation of transcription factors involved in T-cell activation. Using electrophoretic mobility shift assays, we have demonstrated that TNP-470 amplifies and extends the DNA-binding activity of nuclear factor-AT, nuclear factor-KB, and activation protein-1 in T cells. Furthermore, the angioinhibin significantly increased the secretion of IL-2 and IL-4. Our data demonstrate that TNP-470 amplifies the activation of T cells. This effect, whose molecular mechanisms remain to be elucidated, has to be taken into account in the assessment of the antitumor effect of the drug.
Locigno
R
R
Metastasis Research Laboratory, University of Liège, Belgium.
Antoine
N
N
Bours
V
V
Daukandt
M
M
Heinen
E
E
Castronovo
V
V
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D003510:Cyclohexanes; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008854:Microscopy, Electron; D016328:NF-kappa B / Q000096:biosynthesis* / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011485:Protein Binding; D012717:Sesquiterpenes / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D017931:DNA Primers; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012717:Sesquiterpenes; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004247:DNA; D000077609:O-(Chloroacetylcarbamoyl)fumagillol