琥珀酸生育酚诱导癌细胞凋亡：分子途径与结构要求

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

作者信息

Neuzil J, Weber T, Schröder A, Lu M, Ostermann G, Gellert N, Mayne G C, Olejnicka B, Nègre-Salvayre A, Stícha M, Coffey R J, Weber C

机构信息

Institute for Prevention of Cardiovascular Diseases and Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany.

出版信息

FASEB J. 2001 Feb;15(2):403-15. doi: 10.1096/fj.00-0251com.

DOI:10.1096/fj.00-0251com

PMID:11156956

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.

摘要

维生素E类似物α-生育酚琥珀酸酯（α-TOS）可诱导细胞凋亡。我们发现，α-TOS在造血细胞系和癌细胞系中的促凋亡活性涉及对蛋白激酶C（PKC）的抑制，因为佛波酯肉豆蔻酸酯可阻止α-TOS触发的细胞凋亡。更具选择性的效应物表明，α-TOS通过增加蛋白磷酸酶2A（PP2A）的活性来降低PKCα亚型的活性。使用反义寡核苷酸或PKCα过表达证实了PKCα抑制在α-TOS诱导的细胞凋亡中的作用。功能获得或丧失的bcl-2突变体表明，PKC/PP2A对bcl-2活性的调节是α-TOS诱导的促凋亡信号的线粒体靶点。结构类似物显示，α-生育酚部分和琥珀酰部分对于最大化这些效应都是必需的。在患有结肠癌异种移植瘤的小鼠中，α-TOS可使肿瘤生长抑制80%。这体现了一种具有药理学相关性且无已知副作用的化合物对癌细胞的杀伤作用。