Gamma tocopheryl quinone induces apoptosis in cancer cells via caspase-9 activation and cytochrome c release.

Gabriella Calviello, Simona Serini, Fiorella Di Nicuolo, Elisabetta Piccioni, Maria Elena Marcocci, Nicola Giuseppe Maggiano, Paola Palozza, Kh Jones, Dg Cornwell

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Recently, it was suggested the potential role of gamma-tocopheryl quinone (gamma-TQ), an oxidative metabolite of gamma-tocopherol, as a powerful chemotherapeutic agent, since it was shown that this molecule exerts powerful cytotoxic effects, induces apoptosis and escapes drug resistance in human acute lymphoblastic leukemia and promyelocytic leukemia cells. We have studied the apoptogenic potential of gamma-TQ in cultured human leukemia HL-60 and colon adenocarcinoma WiDr cells, and in murine thymoma cells growing in vivo in ascites form. The cells were treated with gamma-TQ and apoptosis was evaluated morphologically by acridine-orange staining and cytofluorimetrically by Annexin V binding assay. gamma-TQ-induced apoptosis in a dose- and time-dependent manner in all the cell types tested, although HL-60 and thymoma cells were much more sensitive than WiDr cells. In HL-60 cells apoptosis was mediated by the activation of the caspase-3 cascade. In particular, we observed a time- and dose-dependent increase in the activities of the upstream caspase-9 and caspase-8 and of the downstream caspase-3. The activation of caspase-9 preceded that of caspase-8 and its specific inhibition completely prevented apoptosis. These findings and data showing the precocious release of cytochrome c from mitochondria, a decrease in Bcl-2, and a change in mitochondrial transmembrane potential (Delta psi(m)), all suggest that the intrinsic mitochondrial pathway is primarily involved in the development of gamma-TQ-induced apoptosis. The late activation of caspase-8 and data showing the partial cleavage of pro-apoptotic protein BID suggest that the initial activation of caspase-9 may be potentiated by a feedback amplification loop involving the caspase-8/BID pathway.
Lingua originaleEnglish
pagine (da-a)427-433
Numero di pagine7
RivistaCarcinogenesis
Stato di pubblicazionePubblicato - 2003

Keywords

  • apoptosis
  • cultured cells
  • gamma-tocopheryl quinone

Fingerprint Entra nei temi di ricerca di 'Gamma tocopheryl quinone induces apoptosis in cancer cells via caspase-9 activation and cytochrome c release.'. Insieme formano una fingerprint unica.

Cita questo