Autoschizis: a novel cell death

• Published in: Biochemical pharmacology 2002-05, Vol.63 (10), p.1773-1783
• Main Authors: Jamison, James M., Gilloteaux, Jacques, Taper, Henryk S., Calderon, Pedro Buc, Summers, Jack L.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidants - therapeutic use; Ascorbic Acid - chemistry; Ascorbic Acid - pharmacology; Ascorbic Acid - therapeutic use; Autoschizis; Biological and medical sciences; Cell death; Cell Death - physiology; General aspects; Humans; Medical sciences; Menadione; Necrosis; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Vitamin C; Vitamin K - chemistry; Vitamin K - pharmacology; Vitamin K - therapeutic use; Vitamin K 3
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(02)00904-8

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 2O 2 production, and decreases cellular thiol levels. These effects can be prevented by the addition of catalase to scavenge the H 2O 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.