Journal Article

γ-Tocopheryl quinone induces apoptosis in cancer cells via caspase-9 activation and cytochrome <i>c</i> release

Gabriella Calviello, Fiorella Di Nicuolo, Elisabetta Piccioni, M.Elena Marcocci, Simona Serini, Nicola Maggiano, Kenneth H. Jones, David. G. Cornwell and Paola Palozza

in Carcinogenesis

Volume 24, issue 3, pages 427-433
Published in print March 2003 | ISSN: 0143-3334
Published online March 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/24.3.427
γ-Tocopheryl quinone induces apoptosis in cancer cells via caspase-9 activation and cytochrome c release

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Recently, it was suggested the potential role of γ-tocopheryl quinone (γ-TQ), an oxidative metabolite of γ-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 γ-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 γ-TQ and apoptosis was evaluated morphologically by acridine-orange staining and cytofluorimetrically by Annexin V binding assay. γ-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 (Δψm), all suggest that the intrinsic mitochondrial pathway is primarily involved in the development of γ-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.

Keywords: AMC, 7-amido-4-methylcoumarin; DiOC6(3), 3′-dihexyloxacarbocyanide iodide; DTT, dithiothreitol; ΔΨm, mitochondrial transmembrane potential; MDR, multidrug resistance; α-T, α-tocopherol; δ-T, δ-tocopherol; γ-T, γ-tocopherol; α-TQ, α-tocopherylquinone; δ-TQ, δ-tocopherylquinone; γ-TQ, γ-tocopherylquinone.

Journal Article.  5249 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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