The endogenous oxindoles 5-hydroxyoxindole and isatin are antiproliferative and proapoptotic.
Oxindole-core synthetic molecules are currently being developed as anticancer drugs that target protein tyrosine kinases associated with growth factor receptors. Oxindole, 5-Hydroxyoxindole, and 2, 3-dioxindole [isatin] are natural molecules found in mammalian body fluids and tissues and we addressed the question of similar properties of endogenous oxindoles. 5-Hydroxyoxindole and isatin, but not oxindole, inhibited N1E-115, BALB/c3T3, BBC, PC12, and HL60 proliferation at submicromolar concentrations. Acute treatment with 5-hydroxyoxindole and isatin reduced the activity of extracellular signal regulated protein kinases (ERKs) by 35% at 100 microM and ERK1 activity was strongly inhibited by 5-Hydroxyoxindole at 10 microM. Survival of PMA-differentiated HL60 and FGF(2)-differentiated PC12 cells was not affected by 5-Hydroxyoxindole and isatin treatment, suggesting that endogenous oxindoles interact with growth factors signaling. The physiological implications of these data and the potential utility of 5-Hydroxyoxindole and isatin as antitumor agents are discussed.
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Laboratoire CRRET, UPRESA CNRS 7053, University Paris 12 Val-de-Marne, Avenue du Général de Gaulle, Créteil cedex, 94010, France.
Tournaire
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Barritault
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Crumeyrolle-Arias
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007510:Isatin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D007211:Indoles; D007510:Isatin