Caspase-independent necrotic cell death induced by a radiosensitizer, 8-nitrocaffeine.

Abstract

Molecular mechanisms of apoptosis have been extensively studied, but little is known about non-apoptotic cell death. To study the mechanism of non-apoptotic cell death, we searched for non-apoptotic cell death inducers for U937 cells, which are highly sensitive to apoptosis induction by various stimuli. We found that 8-nitrocaffeine and its analog, which are candidate radiosensitizers for cancer therapy, induced exclusively caspase-independent necrotic cell death in cell lines such as U937, HL-60, K562 and Jurkat. The 8-nitrocaffeine-induced necrotic cell death was mediated by reactive oxygen species (ROS) because (i) ROS were produced in the 8-nitrocaffeine-treated cells, (ii) ROS scavengers inhibited the caspase-independent necrotic cell death induced by 8-nitrocaffeine, and (iii) the necrotic cell death was completely suppressed in hypoxic cells. Cells selected for resistance to nitrocaffeine showed cross resistance to CH-11, an anti-Fas antibody, suggesting that the necrotic process plays an important role in Fas-mediated cell death in this cell line. Since cancer cells are often derived from a selected population of cells resistant to apoptosis, inducers of necrotic cell death could be beneficial to kill cancer cells that have acquired resistance to apoptosis-induction therapy.

• Authors: Mikihiko Naito, Chizuko Hashimoto, Shigeki Masui, Takashi Tsuruo
• Journal: Cancer science (Cancer Sci) Vol. 95 Issue 4 Pg. 361-6 (Apr 2004) ISSN: 1347-9032 [Print] England
• PMID: 15072596 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,7-dimethyl-8-nitroxanthine
• 8-nitrocaffeine
• Antibodies, Monoclonal
• Cysteine Proteinase Inhibitors
• Free Radical Scavengers
• Radiation-Sensitizing Agents
• Reactive Oxygen Species
• Xanthines
• fas Receptor
• Caffeine
• Antimycin A
• Etoposide
• Caspases

Topics

• Antibodies, Monoclonal (pharmacology)
• Antimycin A (pharmacology)
• Caffeine (analogs & derivatives, pharmacology)
• Caspases (physiology)
• Cell Death (drug effects)
• Cell Hypoxia
• Cell Line, Tumor (cytology, drug effects)
• Cysteine Proteinase Inhibitors (pharmacology)
• Drug Resistance, Multiple
• Etoposide (pharmacology)
• Fibrosarcoma (pathology)
• Free Radical Scavengers (pharmacology)
• HL-60 Cells (cytology, drug effects)
• Humans
• Jurkat Cells (cytology, drug effects)
• K562 Cells (cytology, drug effects)
• Necrosis
• Radiation-Sensitizing Agents (pharmacology)
• Reactive Oxygen Species (metabolism)
• U937 Cells (cytology, drug effects)
• Xanthines (pharmacology)
• fas Receptor (immunology, physiology)