ADP-ribosylation inhibitors inhibit cellular RNA synthesis but do not affect expression of manganous superoxide dismutase or heat shock protein 70 in tumor necrosis factor alpha-sensitive and -resistant tumor cells.
We have shown that the cytotoxic response of TNF-sensitive L929 cells and TNF-resistant EMT-6 cells to TNF-alpha can be modulated by ADP-ribosylation inhibitors independently of ADP-ribosylation rates. To explore the possibility that these inhibitors modulate TNF cytotoxicity by interfering with cellular protective mechanisms, we evaluated their effects on general RNA synthesis and on mRNA expression of two proposed protective genes, manganous superoxide dismutase (MnSOD) and heat shock protein 70 (hsp70). We found that ADP-ribosylation inhibitors could inhibit general RNA synthesis in a dose-dependent fashion to a similar extent in both EMT-6 and L929 cells, although these inhibitors increased or decreased the sensitivity of the cells to TNF, respectively. In EMT-6 cells, combination of actinomycin D with these inhibitors further inhibited the RNA synthesis rate, and it actually decreased the TNF sensitivity of the EMT-6 cells. Furthermore, the expression of MnSOD or hsp70 was not regulated by these inhibitors. Thus, TNF resistance must depend on other mechanisms in addition to the expression of these protective genes.
Department of Tumor Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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Hung
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Klostergaard
D000818:Animals; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D051379:Mice; D008969:Molecular Sequence Data; D009536:Niacinamide / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012313:RNA / Q000096:biosynthesis*; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D001549:Benzamides; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; D012313:RNA; C025160:3-aminobenzamide; D013482:Superoxide Dismutase