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

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.