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

• Published in: The FASEB journal Vol. 15; no. 2; p. 403
• Main Authors: Neuzil, J., Weber, T., Schroder, A., Lu, M., Ostermann, G., Gellert, N., Mayne, G.C., Olejnicka, Beata, Negre-Salvayre, A., Sticha, M., Coffey, R.J., Weber, C.
• Format: Journal Article
• Language: English
• Published: 01-02-2001
• Subjects: Colon cancer; MEDICIN; MEDICINE; Programmed cell death; Protein kinase C; Vitamin E succinate
• ISSN: 1530-6860; 0892-6638
• DOI: 10.1096/fj.00-0251com

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.