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Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA
Author(s) -
Berndtsson Maria,
Hägg Maria,
Panaretakis Theocharis,
Havelka Aleksandra Mandic,
Shoshan Maria C.,
Linder Stig
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22132
Subject(s) - cisplatin , apoptosis , dna damage , reactive oxygen species , superoxide , programmed cell death , chemistry , microbiology and biotechnology , biology , dna , biochemistry , genetics , chemotherapy , enzyme
Cisplatin is a broad‐spectrum anticancer drug that is also widely used in experimental studies on DNA damage‐induced apoptosis. Induction of apoptosis within 24–48 hr requires cisplatin concentrations that are at least one order of magnitude higher than the IC 50 . Here, we show that such high, apoptosis‐inducing cisplatin concentrations induce cellular superoxide formation and that apoptosis is inhibited by superoxide scavengers. The same concentration limit and the requirement for superoxide are also true for induction of caspase activation in enucleated cells (cytoplasts), showing that cisplatin‐induced apoptosis occurs independently of nuclear DNA damage. In contrast, lower cisplatin concentrations, which do not induce acute apoptosis, are sufficient for induction of DNA damage signaling. We propose that the antiproliferative effects of cisplatin at IC 50 doses involve premature senescence and secondary, nonstress‐induced apoptosis. The higher doses currently used in in vitro studies lead to acute, stress‐induced apoptosis that involves induction of superoxide but is largely DNA damage‐independent. © 2006 Wiley‐Liss, Inc.