ABSTRACT
Reduced glutathione (GSH), a ubiquitous thiol-containing tripeptide, is unanimously recognized to play a central role in cell biology. It is highly implicated in the cellular defense against xenobiotics and naturally occurring deleterious compounds such as free radicals and hydroperoxides. Consequently, GSH is an essential actor in several human diseases including cancer and cardio-vascular diseases. Its implication in oncogenesis has led to the development of new strategies to improve both prevention and treatment of cancer. The present review proposes an in depth analysis or our current knowledge of the relations between GSH and cancer.
Subject(s)
Glutathione/metabolism , Neoplasms/prevention & control , Animals , Humans , Neoplasms/metabolism , Neoplasms/pathologyABSTRACT
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.
Subject(s)
Angiogenesis Inhibitors/pharmacology , DNA-Binding Proteins/biosynthesis , NF-kappa B/biosynthesis , Nuclear Proteins , Sesquiterpenes/pharmacology , T-Lymphocytes/drug effects , Transcription Factor AP-1/biosynthesis , Transcription Factors/biosynthesis , Base Sequence , Cells, Cultured , Cyclohexanes , DNA/metabolism , DNA Primers , DNA-Binding Proteins/metabolism , Humans , Lymphocyte Activation/drug effects , Microscopy, Electron , NF-kappa B/metabolism , NFATC Transcription Factors , O-(Chloroacetylcarbamoyl)fumagillol , Protein Binding , T-Lymphocytes/immunology , T-Lymphocytes/ultrastructure , Transcription Factor AP-1/metabolism , Transcription Factors/metabolismABSTRACT
BACKGROUND: AGM-1470 is a newly synthesized molecule developed as an analog of the potent anti-angiogenic fumagillin. Its efficacy in restraining tumor growth in vivo and the absence of major side effects have already led to phase I clinical trials in patients with solid cancers. However, neither the exact mechanisms of action of AGM-1470 nor its effects on the host of normal cells have been extensively studied. Recently, we showed that AGM-1470 enhanced the proliferation of B lymphocytes in the presence of T cells. Since AGM-1470 could potentially be used in patients with lymphoma, it was urgent to test the effect of the molecule on the proliferation of tumor lymphocytes. METHODS: The possible effect of AGM-1470 on the proliferation of normal or tumor lymphocytes was evaluated by thymidine-incorporated assays. Normal T and B lymphocytes were purified from human tonsils. The tumor lymphocytes used in the study were Molt 3, Molt 4 and Jurkatt cell lines for the T lineage and Daudi and Radji cell lines for the B lineage. RESULTS: As shown previously, AGM-1470 stimulates the proliferation of normal B lymphocytes through an action on normal T cells. THe angioinhibin was ineffective ont eh proliferation of both T and B transformed cells. Moreover, in the presence of the drug, tumor T cells co-cultured with normal B lymphocytes did not induce any increase in B cell proliferation, as previously observed with normal T lymphocytes. Inversely, tumor B cells co-cultured with normal T lymphocytes were insensitive to the drug. CONCLUSIONS: Our results demonstrate that AGM-1470 is ineffective on lymphoid tumor cell proliferation and could potentially be safely administered to lymphoma patients.
