Induction of cancer cell apoptosis by a-tocopheryl succinate: Molecular pathways and structural requirements

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