TNP-470, a potent angiogenesis inhibitor, amplifies human T lymphocyte activation through an induction of nuclear factor-kappa B, 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 an d its lack of major side effects have been demonstrated in several animal m odels 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 proli feration through an action on T cells. In this study, we examined the cellu lar and molecular modifications induced by TNP-470 in normal human T lympho cytes. 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 signif icant increase of the nuclear size as well as major nuclear chromatin decon densation. This observation indicated that TNP-470 amplified T-cell activat ion and led us to investigate its effects on the activation of transcriptio n factors involved in T-cell activation. Using electrophoretic mobility shi ft assays, we have demonstrated that TNP-470 amplifies and extends the DNA- binding activity of nuclear factor-AT, nuclear factor-kappa B, and activati on protein-1 in T cells. Furthermore, the angioinhibin significantly increa sed the secretion of IL-2 and IL-4. Our data demonstrate that TNP-470 ampli fies the activation of T cells. This effect, whose molecular mechanisms rem ain to be elucidated, has to be taken into account in the assessment of the antitumor effect of the drug.