Induction of cancer cell apoptosis by α-tocopheryl succinate: molecular pathways and structural requirements

Jirí Neuzil, Tobias Weber, Andreas Schröder, Min Lu, Georg Ostermann, Nina Gellert, George C. Mayne, Beata Olejnicka, Anne Nègre-Salvayre, Martin Stícha, Robert J. Coffey, Christian Weber

Research output: Contribution to journalArticlepeer-review

278 Citations (Scopus)

Abstract

The vitamin E analog α-tocopheryl succinate (α-TOS) can induce apoptosis. We show that the proapoptotic activity of α-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented α-TOS-triggered apoptosis. More selective effectors indicated that α-TOS reduced PKCα isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCα inhibition in α-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCα overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of α-TOS-induced proapoptotic signals. Structural analogs revealed that α-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, α-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.

Original languageEnglish
Pages (from-to)403-415
Number of pages13
JournalFASEB Journal
Volume15
Issue number2
DOIs
Publication statusPublished - Jan 2001

Keywords

  • Colon cancer
  • Programmed cell death
  • Protein kinase C
  • Vitamin E succinate

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