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.
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Autoschizis exhibits considerable mechanistic overlap with well-established forms of regulated cell death.
“terms mostly referring to morphological features of cellular demise and/or indicating considerable mechanistic overlap with well-established RCD forms, such as autoschizis [1064, 1065], should be dismissed.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [1065]
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- Authors
- Jamison, J. M., Gilloteaux, J., Taper, H. S., Calderon, P. B., & Summers, J. L.
- Affiliations
- Summa Health System (US)
- UCLouvain (BE)
- Corresponding author
- Jamison, James M.
- ORCID
- Gilloteaux, Jacques
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 63
- Issue
- 10
- Pages
- 1773-1783
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2042308152
- Cited by
- 87
- References
- 67
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 1 · 2023: 3 · 2021: 3 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 3 · 2014: 7 · 2013: 4 · 2012: 3
- FWCI
- 0.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- vitamin C, menadione, synergistic antitumor effect, necrosis, DNase I, DNase II, oxidative stress, hydrogen peroxide, catalase, intracellular calcium, thiol depletion, G1/S cell cycle arrest, cancer cell death, redox cycling
- MeSH terms
- Animals, Antioxidants, Ascorbic Acid, Humans, Necrosis, Neoplasms, Vitamin K, Cell Death, Oxidative Stress
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