Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA
Acute apoptosis by cisplatin requires induction of reactive oxygen species but is not associated with damage to nuclear DNA
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DOI：
10.1002/ijc.22132
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发表时间：
2007-01-01
影响因子：
6.4
通讯作者：
Linder, Stig
中科院分区：
文献类型：
--
作者：
Berndtsson, Maria;Hagg, Maria;Linder, Stig
顺铂是一种广谱抗癌药物，也广泛用于DNA损伤诱导凋亡的实验研究。在24 - 48小时内诱导凋亡所需的顺铂浓度比半数抑制浓度（IC50）至少高一个数量级。在此，我们表明这种高的、诱导凋亡的顺铂浓度会诱导细胞超氧化物的形成，并且凋亡会被超氧化物清除剂抑制。对于去核细胞（胞质体）中半胱天冬酶激活的诱导，同样的浓度界限和对超氧化物的需求也是如此，这表明顺铂诱导的凋亡独立于核DNA损伤发生。相反，不诱导急性凋亡的较低顺铂浓度足以诱导DNA损伤信号传导。我们提出，顺铂在IC50剂量下的抗增殖作用涉及过早衰老和继发性的、非应激诱导的凋亡。目前在体外研究中使用的较高剂量会导致急性的、应激诱导的凋亡，这种凋亡涉及超氧化物的诱导，但在很大程度上与DNA损伤无关。（c）2006威利 - 利斯公司
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 IC50. 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 IC50 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. (c) 2006 Wiley-Liss, Inc.