Aloe-emodin prevents cytokine-induced tumor cell death: the inhibition of auto-toxic nitric oxide release as a potential mechanism.
Aloe-emodin (AE) is a plant-derived hydroxyanthraquinone with potential anticancer activity. We investigated the ability of AE to modulate survival of mouse L929 fibrosarcoma and rat C6 astrocytoma cells through interference with the activation of inducible nitric oxide (NO) synthase (NOS) and subsequent production of tumoricidal free radical NO. Somewhat surprisingly, AE in a dose-dependent manner rescued interferon-gamma + interleukin-1-stimulated L929 cells from NO-dependent killing by reducing their autotoxic NO release. The observed protective effect was less pronounced in C6 cells, due to their higher sensitivity to a direct toxic action of the drug. AE-mediated inhibition of tumor cell NO release coincided with a reduction in cytokine-induced accumulation of transcription and translation products of genes encoding inducible NOS and its transcription factor IRF-1, while activation of NF-kappaB remained unaltered. These data indicate that the influence of AE on tumor growth might be more complex that previously recognized, the net effect being determined by the balance between the two opposing actions of the drug: its capacity to directly kill tumor cells, but also to protect them from NO-mediated toxicity.
Mijatovic
S
S
Department of Neurobiology and Immunology, Institute for Biological Research, 29. Novembra 142, 11000, Belgrade, Serbia and Montenegro. mamas@yubc.net
Maksimovic-Ivanic
D
D
Radovic
J
J
Popadic
D
D
Momcilovic
M
M
Harhaji
L
L
Miljkovic
D
D
Trajkovic
V
V
D000818:Animals; D000880:Anthraquinones; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects; D015536:Down-Regulation; D004642:Emodin / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D050856:Interferon Regulatory Factor-1; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D010750:Phosphoproteins / Q000187:drug effects; D051381:Rats; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D016207:Cytokines; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; C494259:Irf1 protein, rat; D016328:NF-kappa B; D010750:Phosphoproteins; D009569:Nitric Oxide; C518327:aloe emodin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D004642:Emodin