Autoschizis: A novel cell death

Vitamin C (VC) and vitamin K₃ (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 G₁/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.