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dc.contributor.authorGonzález-Santiago, L.-
dc.contributor.authorSuárez, Yajaira-
dc.contributor.authorMuñoz-Alonso, María J.-
dc.contributor.authorCuadrado, Ana-
dc.contributor.authorMartínez, Teresa-
dc.contributor.authorGoya, Luis-
dc.contributor.authorRojas, José María-
dc.contributor.authorMuñoz Terol, Alberto-
dc.identifierdoi: 10.1038/sj.cdd.4401898-
dc.identifierissn: 1350-9047-
dc.identifier.citationCell Death and Differentiation 13(11): 1968-1981 (2006)-
dc.description.abstractAplidin® is an antitumor agent in phase II clinical trials that induces apoptosis through the sustained activation of Jun N-terminal kinase (JNK). We report that Aplidin® alters glutathione homeostasis increasing the ratio of oxidized to reduced forms (GSSG/GSH). Aplidin® generates reactive oxygen species and disrupts the mitochondrial membrane potential. Exogenous GSH inhibits these effects and also JNK activation and cell death. We found two mechanisms by which Aplidin® activates JNK: rapid activation of Rac1 small GTPase and downregulation of MKP-1 phosphatase. Rac1 activation was diminished by GSH and enhanced by L-buthionine (SR)-sulfoximine, which inhibits GSH synthesis. Downregulation of Rac1 by transfection of small interfering RNA (siRNA) duplexes or the use of a specific Rac1 inhibitor decreased Aplidin®-induced JNK activation and cytotoxicity. Our results show that Aplidin® induces apoptosis by increasing the GSSG/GSH ratio, a necessary step for induction of oxidative stress and sustained JNK activation through Rac1 activation and MKP-1 downregulation.-
dc.description.sponsorshipThis study was supported in part by Grant SAF04- 01015 (to AM) and SAF03-02604 (to JMR) from Ministerio de Educación y Ciencia and FIS03-C03/10 and Intramural ISCIII (03/ESP27) from Instituto de Salud Carlos III.-
dc.publisherNature Publishing Group-
dc.titleAplidin® induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation-
dc.description.versionPeer Reviewed-
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