Autoschizis: a novel cell death.
摘要：
Vitamin C (VC) and vitamin K (VK) administered in a VC:VK ratio of 100:1 exhibit synergistic antitumor activity and preferentially kill tumor cells by autoschizis, a novel type of necrosis characterized by exaggerated membrane damage and progressive loss of organelle-free cytoplasm through a series of self-excisions. During this process, the nucleus becomes smaller, cell size decreases one-half to one-third of its original size, and most organelles surround an intact nucleus in a narrow rim of cytoplasm. While the mitochondria are condensed, tumor cell death does not result from ATP depletion. However, vitamin treatment induces a G/S block, diminishes DNA synthesis, increases HO production, and decreases cellular thiol levels. These effects can be prevented by the addition of catalase to scavenge the HO. There is a concurrent 8- to 10-fold increase in intracellular Ca levels. Electrophoretic analysis of DNA reveals degradation due to the caspase-3-independent reactivation of deoxyribonuclease I and II (DNase I, DNase II). Redox cycling of the vitamins is believed to increase oxidative stress until it surpasses the reducing ability of cellular thiols and induces Ca release, which triggers activation of Ca-dependent DNase and leads to degradation of DNA. Recent experiments indicate that oral VC:VK increases the life-span of tumor-bearing nude mice and significantly reduces the growth rate of solid tumors without any significant toxicity by reactivating DNase I and II and inducing autoschizis. This report discusses the mechanisms of action employed by these vitamins to induce tumor-specific death by autoschizis.
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关键词：
-threo-hex-2-enoic acid γ-lactone VK vitamin K 2-methyl-1 4-naphthoquinone menadione DNase I deoxyribonuclease I DNase II
DOI：
10.1016/S0006-2952(02)00904-8
被引量：
年份：
2002
Elsevier
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