Effects on Proliferation

RESPONSES OF CULTURED CELLS TO ASCORBATE 3.1. Effects on Proliferation 

As already mentioned in Section 2, ascorbate stimulates the proliferation of some, but not all tumor cells. Some examples are compiled in Table IV. If effective at all, ascorbate-stimulated proliferation at concentrations 1 mM, usually at 0.2-0.3 mM, i.e., at or slightly above the physiological serum level (Bergsten et al., 1994). The ascorbate dependency, however, appears to be highly variable even with closely related cells. 

Park et al. (1971) compared the effects of ascorbate on mouse plasmacytoma cells with that on normal bone marrow cells forming granulocytic colonies. Only the plasmacytoma cells responded with marked proliferation. This, however, does not imply that myeloic stem cells in general are unresponsive to ascorbate. The growth of the human promyeloic tumor cell line HL-60 was stimulated by ascorbate (Alcain et al., 1990). Similarly, bone marrow cells from a variety of acute myeloid leukemia patients responded with growth, or growth inhibition or remained unaffected (Park et al, 1992). In this context it should be stressed that inhibition of 

Human forearm skin fibroblasts (asc 2-P) 0.01-1 mM Hata and Senoo, 1989 

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Many of these intracellular events are critical to the prohferative effects of CXCL12. For example, the CXCL12-induced effect on proliferation is dependent on calcium. Pre-treatment of pituitary adenoma cells with BAPTA-AM abohshes the CXCL12-induced increase in prohferation (Florio et al. 2006). The increase in proliferation also requires activation of Erk 1/2, as pre-treatment with PD98059, a MEK inhibitor, blocks the proliferative effect of CXCL12, and this is correlated with a decrease in Erk 1/2 phosphorylation. Similarly, the proliferative effects of... 

Li, L., Braiteh, F.S., and Kurzrock, R., Liposome-encapsulated curcumin in vitro and in vivo effects on proliferation, Apopf. Signal. Angiogen. Cancer, 104, 1322, 2005. Socaciu, C., Jessel, R., and Diehl, H.A., Competitive carotenoid and cholesterol incorporation into liposomes effects on membrane phase transition, fluidity, polarity... 

Lycopene Effects on Proliferation, Cell Cycle, and Apoptosis.445... 

Nakaoji, K., Nayeshiro, H., Tanahashi, T., Su, Y. and Nagakura, N. 1997. Bis-benzylisoquinoline alkaloids from Stephania cepharantha and their effects on proliferation of cultured cells from the Murine Hair apparatus. Planta Medica, 63 425 28. 

Methotrexate s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, inhibition of proinflammatory cytokines linked to rheumatoid synovitis has been shown, leading to decreased inflammation seen with rheumatoid arthritis. 

Glucocorticoids (corticosteroids) were the first hormonal agents recognized as having lympholytic properties. Administration of any glucocorticoid reduces the size and lymphoid content of the lymph nodes and spleen, although it has no toxic effect on proliferating myeloid or erythroid stem cells in the bone marrow. 

In an effort to investigate antioxidant constituents with antiproliferative effects in rat vascular smooth muscle cells (VSMC), broussoflavan A (36) [49], broussoflavonols F (45) [50] and G (46) [51], and broussoaurone A (48) [49] were found to inhibit the Fe2+-induced thiobarbituric acid-reactive substance formation in rat brain homogenate. Furthermore, broussoflavonols F (45) and G (46) inhibited fetal calf serum-, 5-hydroxytryptamine-, or ADP-induced [3H]thymidine incorporation into rat VSMC [45]. Antioxidant activities and inhibitory effects on proliferation of rat VSMC with potent antiplatelet activities of 45 and 46 may be useful for vascular diseases and atherosclerosis [43,45]. 

Li L, Braiteh FS, Kurzrock R. 2005. Liposome-encapsulated curcumin in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 104 1322-1331. 

Skin safety of niosomes was tested in a number of studies. As an example, the toxicity of polyoxyethylene alkyl ether vesicles containing Ci2-i8 alkyl chains and 3 and 7 oxyethylene units was assessed by measuring the effect on proliferation of cultured human keratinocytes [47]. It was found that the length of either polyoxyethylene headgroup or alkyl chain had only a minor influence on keratinocyte proliferation. However, the ether surfactants were much more toxic than esters tested in this study. The concentrations of ether surfactants required to inhibit cell proliferation by 50% were 10-fold lower than for ester surfactants. Neither the HLB nor the critical micelle concentration values or cholesterol content affected keratinocyte proliferation. 

Yilmaz A, Bieler G, Spertini O, Lejeune FL, Ruegg C. Pulse treatment of human vascular endothelial cells with high doses of tumor necrosis factor and interferon-gamma results in simultaneous synergistic and reversible effects on proliferation and morphology. Int J Cancer 1998 77 592-599. 

Cell studies on scaffolds of nano- and submicrometer-scaled fibers have shown that these dimensions promote not only cell adhesion, but also have beneficial effects on proliferation and differentiation of cells [174-177], These effects are more prominent with decreasing fiber diameters. It seems relevant that the cells can be guided and bridged by the artificial fibers. Meshes with aligned fibers are particularly promising, e.g., for guiding the growth of nerve cells (Fig. 8) [178],... 

Pro-inflammatory cytokines are important mediators of inflammation and tissue destruction. This section describes two cell-based assays that were used to screen for inhibitors of cytokine production and some of the compounds discovered using these screens. The two screens were important elements of a collaboration between Xenova Ltd and the Suntory Institute of Biomedical Research to find microbial metabolites with potential utility for the treatment of rheumatoid arthritis. Both screens were cell stimulatory assays with similar formats, the principle of which is illustrated in Figure 3. Treatment of cells with a particular stimulus activates a signal transduction pathway, one of the end results of which is production of a cytokine, which is secreted into the assay medium. After a separation step, the cytokine of interest is measured quantitatively in the supernatant by dissociation enhanced lanthanide fluorescence immunoassay (DELFIA) using a europium-labeled tertiary antibody. At the same time, cytotoxic properties of test substances are determined by assessing their effect on proliferation of the separated cells. 

Deferoxamine has a strong depressant effect on proliferation of bone marrow cultures in vitro (72). On the other hand, deferoxamine improves hemopoiesis in patients with anemia, for example in rheumatoid arthritis, hemolysis, or myelodysplastic sjmdromes, and reduces transfusion dependency (73-78). The mechanism is unknown, but increased erythropoietin responsiveness secondary to iron chelation may play a role (77). 

Breier JM, Radio NM, Mundy WR, et al. Development of a high-throughput screening assay for chemical effects on proliferation and viability of immortalized human neural progenitor cells. Toxicol Sci. 2008 105 119-133. 

M. Recombinant human tumor necrosis factor-alpha Effects on proliferation of normal and transformed cells in vitro. Science 230, 943-945 (1985). 

Greene, L. A., and Rukenstein, A, ( 9Sl). Regulation of acctyl-choline.sterase activity by nerve growth factor Role of transcription and dissociation from effects on proliferation and neurite outgrowth, J. Biol. Chem. 256,6363-6367,... 

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