Autoschizis: a novel cell death.

Abstract

Vitamin C (VC) and vitamin K(3) (VK(3)) administered in a VC:VK(3) 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 H(2)O(2) production, and decreases cellular thiol levels. These effects can be prevented by the addition of catalase to scavenge the H(2)O(2). There is a concurrent 8- to 10-fold increase in intracellular Ca(2+) 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(2+) release, which triggers activation of Ca(2+)-dependent DNase and leads to degradation of DNA. Recent experiments indicate that oral VC:VK(3) 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.

• Authors: James M Jamison, Jacques Gilloteaux, Henryk S Taper, Pedro Buc Calderon, Jack L Summers
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 63 Issue 10 Pg. 1773-83 (May 15 2002) ISSN: 0006-2952 [Print] England
• PMID: 12034362 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antioxidants
• Vitamin K
• Ascorbic Acid

Topics

• Animals
• Antioxidants (chemistry, pharmacology, therapeutic use)
• Ascorbic Acid (chemistry, pharmacology, therapeutic use)
• Cell Death (physiology)
• Humans
• Necrosis
• Neoplasms (drug therapy, metabolism, pathology)
• Oxidative Stress (drug effects)
• Vitamin K (chemistry, pharmacology, therapeutic use)