Open AccessCaspase‐independent necrotic cell death induced by a radiosensitizer, 8‐nitrocaffeine
Author(s) -
Naito Mikihiko,
Hashimoto Chizuko,
Masui Shigeki,
Tsuruo Takashi
Publication year - 2004
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2004.tb03216.x
Subject(s) - programmed cell death , apoptosis , uvb induced apoptosis , jurkat cells , biology , cell culture , necrosis , cancer cell , caspase , cancer research , u937 cell , cell , microbiology and biotechnology , immunology , cancer , t cell , biochemistry , immune system , genetics
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.