Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. |
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| Authors: | J Neuzil T Weber A Schr?der M Lu G Ostermann N Gellert G C Mayne B Olejnicka A Nègre-Salvayre M Stícha R J Coffey C Weber |
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| Institution: | Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany. jneuzil@klp.med.uni-muenchen.de |
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| Abstract: | The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects. |
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