Autoschizis: a novel cell death
(2002) Biochemical Pharmacology — Vol. 63, n° 10, p. 1773-1783 (2002)
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- Vitamin C (VC) and vitamin K-3 (VK3) administered in a VC:VK3 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(1)/S block, diminishes DNA synthesis, increases H2O2 production, and decreases cellular thiol levels. These effects can be prevented by the addition of catalase to scavenge the H2O2. There is a concurrent 8- to 10-fold increase in intracellular Ca2+ 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 Ca2+ release, which triggers activation of Ca2+-dependent DNase and leads to degradation of DNA. Recent experiments indicate that oral VC:VK3 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. (C) 2002 Elsevier Science Inc. All rights reserved.
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Jamison, J. M., Gilloteaux, J., Taper, H. S., Buc Calderon, P., & Summers, J. L. (2002). Autoschizis: a novel cell death. Biochemical Pharmacology, 63(10), 1773-1783. https://doi.org/10.1016/S0006-2952(02)00904-8 (Original work published 2002)