Our results suggest that paclitaxel/ceramide combination therapy may be an attractive alternative to conventional methods of chemotherapy for head and neck cancer, and should be further explored.
Recent studies have established the ability ofhuman B lymphocytes to undergo GI-phase cell cycle progression and subsequent DNA synthesis upon exposure to factor(s) present in media conditioned by lectin-stimulated mononuclear cells. Procedures for the isolation of such a cytokine have been the focus of the present investigation. Conditioned medium from cells stimulated by lectin for 72 hr was fractionated by ammonium sulfate precipitation, ion-exchange chromatography, and gel filtration chromatography. During the isolation procedure the proliferation-stimulating activity of the column fractions was assayed concurrently on purified human T cells, purified human B cells, and murine thymocytes. T cell and B cell stimulatory factors present in the initial conditioned medium were found to copurify during ammonium sulfate precipitation, DEAE-Sephadex chromatography, and Bio-Gel P-30 gel filtration. However, partial separation of these two activities was achieved after Bio-Gel P-100 gel filtration. Analytic polyacrylamide gel electrophoresis of radiolabeled Bio-Gel P-100 column fractions demonstrated a distinct protein band of 14,000-15,000 daltons in those column fractions predominantly supporting T cell growth and a distinct protein band of 12,000-13,000 daltons for those fractions predominantly supporting B cell growth. The fractions associated with B cell mitogenic activity induced B cell S-phase entry in a proportion of B lymphocytes in the absence of any detectable IgM secretion.Soluble growth factors for normal epithelial, fibroblastic, hematopoietic, and lymphoid cells have been described and characterized (1). The best delineated lymphoid cell growth factors have been termed interleukin 1 (IL-1) and interleukin 2 (IL-2) (2). These factors have been demonstrated to function in a bimodal amplification network resulting in the proliferative expansion of activated T cells (3,4). The role of soluble factors in the induction of B cell proliferation has also recently been investigated (5-10). Studies have confirmed the capability ofculturing normal, Epstein-Barr virus-negative, B lymphoblastoid cell lines by using exogenously supplied growth-promoting agents (7,8). Investigation into the sources for these B cell growth-promoting agents has revealed that conditioned media derived from several culture systems contains the molecule(s) capable of stimulating B cell proliferation. Both lectin-stimulated normal mononuclear cells (derived from human peripheral blood or murine spleen cell preparations) and antigen-restricted normal helper T cells (grown in the presence of irradiated accessory cells) have been' shown to produce factors capable of supporting B cell growth (5-7). Similar B cell growth-supporting factors have also been observed in conditioned media from phorbol ester-stimulated EL-4 thymoma cells and lectin-stimulated T hybridoma cells (FS6 14.13) (7, 9). Yet it has been well documented that these conditioned media preparations contain multiple functional biological activities. The question that become...
analysis was performed for the determination of generation of reactive oxygen species. Results: Arsenite induced the activation of AKT at both Ser473 and Thr308, and its downstream effector eNOS in cultured human keratinocytes. Arsenite also induced phosphorylation of p38. PI-3-kinase inhibitors, Wortmannin and LY294002 inhibited arsenite-induced phosphorylation of AKT and eNOS but had no effect on phosphorylation of p38. Interestingly, however, SB203580, a known p38 inhibitor, completely inhibited arsenite-induced phosphorylation of AKT and eNOS. Arsenite induced generation of reactive oxygen species and inactivated phosphatase activity, but did not activate EGF receptor tyrosine phosphorylation. Conclusions: Collectively, our data indicate that arsenite induces activation of AKT and eNOS, via PI-3-kinase and p38 pathway, likely bypassing the activation of EGF receptor in cultured human keratinocytes. AbstractBackground: Arsenic has been considered as a carcinogen. Recently the issue of arsenic in drinking water raised an unprecedented social concern on human health, and yet the molecular mechanisms through which arsenic induces cancer remain unknown. Activation of cell survival pathway leading to the activation of eNOS has been associated with various types of cancer. The objective of this study was to investigate the pathway leading to the activation of eNOS in response to arsenite using human keratinocytes. Materials and Methods: Cultured keratinocytes (HaCat cells) were exposed to arsenite with or without pretreatment of various inhibitors. Western blot analysis was performed to determine the activation of p38, AKT, eNOS. EGFR tyrosine phosphorylation was detected by immunoprecipitation and Western blot analysis. pNPP assay was used to measure phosphatase activity in cell lysate. FACS
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