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

doi:10.1096/fj.00-0251com

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

College of Medicine and Public Health

Research output: Contribution to journal › Article › peer-review

279 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 language	English
Pages (from-to)	403-415
Number of pages	13
Journal	FASEB Journal
Volume	15
Issue number	2
DOIs	https://doi.org/10.1096/fj.00-0251com
Publication status	Published - Jan 2001

Keywords

Colon cancer
Programmed cell death
Protein kinase C
Vitamin E succinate

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

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.",

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AU - Neuzil, Jirí

AU - Weber, Tobias

AU - Schröder, Andreas

AU - Lu, Min

AU - Ostermann, Georg

AU - Gellert, Nina

AU - Mayne, George C.

AU - Olejnicka, Beata

AU - Nègre-Salvayre, Anne

AU - Stícha, Martin

AU - Coffey, Robert J.

AU - Weber, Christian

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N2 - 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.

AB - 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.

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KW - Programmed cell death

KW - Protein kinase C

KW - Vitamin E succinate

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

Abstract

Keywords

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