European Journal of Pharmacology . 1 March 2011Copyright © 2011 Elsevier B.V.
Martínez-Serra J, Maffiotte E, Martín J, Bex T, Navarro-Palou M, Ros T, Plazas JM, Vögler O, Gutiérrez A, Amat JC, Ramos R, Saus C, Ginés J, Alemany R, Diaz M, Besalduch J.
Department of Hematology, University Hospital of Son Dureta, c/Andrea Doria, nº 55, Palma de Mallorca, Spain; and, Palma de Mallorca, Spain; IUNICS - University Research Institute of Health Sciences.
Abstract
Trabectedin, a naturally occurring substance isolated from the Caribbean marine invertebrate Ecteinascidia turbinata, is the active compound of the antitumor drug Yondelis®. The mechanism of action of Trabectedin has been attributed to interactions with the minor groove of the DNA double helix, thereby affecting transcription of different genes involved in DNA repair and thus facilitating lethal DNA strand breaks. Nevertheless, the existence of other clinically important molecular mechanisms has not yet been fully explored. In this paper we demonstrate how Yondelis®, apart from activating the caspase-8-dependent cascade of apoptosis, sensitizes cancer cells to Fas-mediated cell death at achievable concentrations similar to those found in the plasma of patients. In addition we show that the facilitated apoptosis activated through the Fas death receptor, is associated with a significant increase of membrane Fas/FasL, as well as the modulation of accessory proteins regulating this route, such as FLIP (L) or Akt. Thus, our results propose that the sensitization of the death receptor pathway is an essential mechanism amplifying the cytotoxic properties of Yondelis® that could explain the hepatotoxicity observed in patients treated with this drug. Finally, we also show how the use of dexamethasone as a prophylactic agent that protects against hepatotoxicity induced by Yondelis® may also inhibit some of the cytotoxic properties described in this work.
The study of this important mechanism of action should set up the basis for reassessing clinical therapy with Yondelis® in order to improve antitumor treatment outcome.
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P.D.: Un receptor asociado a la muerte natural de las células, el CD95, puede ser uno de los responsables del crecimiento incontrolado de tumores cancerosos, por lo que bloquear la actividad de este receptor podría detener e incluso revertir el crecimiento de los tumores en tejido humano, según una investigación de la Universidad de Chicago y de la Universidad de Northwestern, publicada en Nature.
http://www.galenoscopio.org/noticias-interesantes/1138-un-receptor-asociado-a-la-apoptosis-celular-puede-ser-causa-del-crecimiento-tumoral
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