Caspase inhibition switches doxorubicin-induced apoptosis to senescence
Caspase inhibition switches doxorubicin-induced apoptosis to senescence
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DOI：
10.1038/sj.onc.1206366
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发表时间：
2003-05-08
期刊：
影响因子：
8
通讯作者：
Mirkin, BL
中科院分区：
文献类型：
--
作者：
Rebbaa, A;Zheng, X;Mirkin, BL
通常认为细胞凋亡的抑制是化疗耐药的主要决定因素。然而，最近的研究结果表明，半胱天冬酶抑制剂不能保护癌细胞免受细胞毒性药物的死亡，但可能将药物诱导的细胞凋亡转变为另一种“默认死亡”。这项研究的主要目标是确定“默认死亡”的主要特征以及激活该开关的机制。为此，我们首先研究了阿霉素诱导的假定细胞死亡模式。利用与这些死亡模式相关的分子标记来识别因细胞凋亡抑制而导致的默认死亡。我们的研究结果表明，阿霉素诱导至少三种不同类型的细胞死亡：衰老、细胞凋亡和一种坏死类型，这些细胞死亡类型呈浓度依赖性。 p21/WAF1、激活的 caspase-3 和激活的 Akt 等特定分子标记与这些死亡模式相关。泛 caspase 抑制剂 (Q-VD-OPH) 大大降低了阿霉素诱导的 caspase-3 激活，但不能保护细胞免受药物毒性。阿霉素和 Q-VD-OPH 的组合导致 p21/WAF1 表达和衰老相关的 β-半乳糖苷酶活性增加，但不改变 Akt 激活。总的来说，这些发现表明细胞凋亡的抑制可能导致细胞周期抑制剂表达增加和细胞衰老。
The inhibition of apoptosis is generally believed to be a major determinant of resistance to chemotherapy. However, recent findings have shown that caspase inhibitors do not protect cancer cells from death by cytotoxic agents, but may switch drug-induced apoptosis to an alternative 'default death'. The primary goals of this study were to determine the major characteristics of the 'default death' and the mechanism by which this switch is activated. For this purpose, we first investigated putative cell death modes induced by doxorubicin. Molecular markers associated with these death modes were utilized to identify the default death resulting from the inhibition of apoptosis. Our findings demonstrated that doxorubicin induced at least three distinct types of cell death, senescence, apoptosis and a type of necrosis, which were concentration dependent. Specific molecular markers such as p21/WAF1, activated caspase-3 and activated Akt were associated with these death modes. The pan-caspase inhibitor (Q-VD-OPH) greatly reduced doxorubicin-induced caspase-3 activation but did not protect cells against drug toxicity. The combination of doxorubicin and Q-VD-OPH caused an increased expression of p21/WAF1 and senescence -associated -beta-galactosidase activity, but did not alter Akt activation. Collectively, these findings suggest that the inhibition of apoptosis may lead to an increased expression of cell cycle inhibitors and cellular senescence.