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

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.