herbimycin and Leukemia

Topics: Animals; Antibodies, Monoclonal; Benzoquinones; Carbazoles; Drug Design; Enzyme Inhibitors; fms-Like Tyrosine Kinase 3; Furans; Humans; Indoles; Lactams, Macrocyclic; Leukemia; Mutation; Piperazines; Pyrroles; Quinazolines; Quinones; Rifabutin; Staurosporine; Sunitinib

CD28/B7 interactions have been demonstrated to provide a co-stimulatory signal for the generation of CD8+ cytotoxic T lymphocytes in the absence of CD4+ T helper cells. The CD28 signals required for induction of cytotoxicity have yet to be described. To investigate further the biochemical signaling pathways associated with CD28-dependent cytotoxicity, we have studied the human thymic leukemia cell line, YT. YT cells kill B7+ targets in a non-major histocompatibility complex (MHC)-restricted, CD28-dependent manner. CD28 ligation on the surface of YT cells caused a rapid increase in the tyrosine phosphorylation of four major cellular substrates with masses estimated to be 110, 95, 85, and 44 kDa. The 110 and 85 kDa substrates were identified as the catalytic and regulatory subunits, respectively, of phosphatidylinositol 3-kinase (PI3-K). Engagement of CD28 caused the rapid receptor association and activation of PI3-K but did not activate phospholipase C gamma. CD28-induced tyrosine phosphorylation and PI3-K activation was independent of p56lck protein tyrosine kinase (PTK) activity (previously reported to be associated with CD28) and was insensitive to inhibition by the PTK inhibitor herbimycin A. Two structurally and mechanistically dissimilar inhibitors of PI3-K, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) also failed to block CD28-dependent tyrosine phosphorylation events or the association of PI3-K with the CD28 receptor. However, both drugs inhibited CD28-dependent cytotoxicity and CD28 receptor associated PI3-K activity with IC50 values similar to the reported IC50 values for PI3-K inhibition. Although herbimycin A did not significantly block the observed CD28-dependent tyrosine phosphorylation or PI3-K activation, herbimycin did block CD28-dependent cytotoxicity in a dose-dependent manner. These data support a role for PI3-K activation in the CD28-dependent initiation of cytotoxic effector function and suggest that a herbimycin sensitive step(s) is either CD28-independent, resides within a PI3-K-independent CD28 signaling pathway, or is downstream of CD28-dependent PI3-K activation.

Topics: Amino Acid Sequence; Androstadienes; Benzoquinones; Calcium; CD28 Antigens; Cytotoxicity, Immunologic; Enzyme Inhibitors; Humans; Immunity, Cellular; Lactams, Macrocyclic; Leukemia; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Molecular Sequence Data; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Phosphotyrosine; Quinones; Rifabutin; Signal Transduction; src-Family Kinases; Tumor Cells, Cultured; Wortmannin

There is increasing evidence that various tumor cells can be induced by differentiation inducers including biological response modifiers, synthetic chemicals and conventional anticancer drugs to differentiate terminally both in vitro and in vivo into cells with normal characteristics. The differentiated cells lose their abilities for proliferation and transplantation in animals. Furthermore, survival times of the animals inoculated with various tumors were found to prolong by administration with the differentiation inducers. These basic findings suggest that induction of terminal tumor cell differentiation is another strategy for cancer therapy: differentiation therapy of cancer. Principles, current status and perspectives of the differentiation therapy of leukemia are reviewed in this article.

Topics: Animals; Benzoquinones; Cell Differentiation; Cytokines; Hemin; Humans; Interferons; Lactams, Macrocyclic; Leukemia; Prednisolone; Quinones; Retinoids; Rifabutin

Topics: Antibiotics, Antineoplastic; Benzoquinones; Cell Differentiation; Genes, abl; Humans; Lactams, Macrocyclic; Leukemia; Protein-Tyrosine Kinases; Quinones; Rifabutin; Tumor Cells, Cultured