1: Biochem Pharmacol  2002 May 15;63(10):1773-83 

Autoschizis: a novel cell death.

Jamison JM, Gilloteaux J, Taper HS, Calderon PB, Summers JL.

Department of Urology, Summa Health System/Northeastern Ohio Universities
College of Medicine, 2209 State Route 44, PO Box 95, Rootstown, OH 44272-0095,
USA. jmj@neoucom.edu

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.

Publication Types:
Review
Review, Tutorial

PMID: 12034362 [PubMed - indexed for MEDLINE]