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 |
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Pages (from-to) | 403-415 |
Number of pages | 13 |
Journal | FASEB Journal |
Volume | 15 |
Issue number | 2 |
DOIs | |
Publication status | Published - Jan 2001 |
Keywords
- Colon cancer
- Programmed cell death
- Protein kinase C
- Vitamin E succinate