Efficient induction of apoptosis by doxorubicin coupled to cell-penetrating peptides compared to unconjugated doxorubicin in the human breast cancer cell line MDA-MB 231
Efficient induction of apoptosis by doxorubicin coupled to cell-penetrating peptides compared to unconjugated doxorubicin in the human breast cancer cell line MDA-MB 231
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DOI：
10.1016/j.canlet.2009.04.044
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发表时间：
2009-11-18
期刊：
影响因子：
9.7
通讯作者：
Kenani, Abderraouf
中科院分区：
文献类型：
--
作者：
Aroui, Sonia;Brahim, Souhir;Kenani, Abderraouf
阿霉素(Dox)是一种治疗各种癌症的常用药物。此前，我们证明了将Dox偶联到细胞穿透肽(CPPs)是克服MDA-MB 231乳腺癌细胞耐药性的一种有价值的策略。在本研究中，我们从诱导细胞凋亡的角度评估了这些Dox结合物(Dox-CPPs)的性质。DOX-CPPS在比未结合的Dox更低的剂量下可诱导MDA-MB 231细胞的凋亡死亡。细胞死亡诱导与Bax寡聚、细胞色素c释放、半胱氨酸天冬氨酸氨基转移酶激活、染色质凝聚和核小体间降解有关。然而，虽然Bcl2过表达在抑制Dox引发的细胞凋亡方面非常有效，但这种抗凋亡蛋白在阻止Dox-CPPs诱导的细胞凋亡方面效果很差。这些观察表明，线粒体破坏是Dox诱导的细胞凋亡信号的主要事件，但Dox-CPP可能能够触发不依赖于线粒体事件的其他凋亡途径。因此，Dox与CCP偶联诱导细胞凋亡的更高效率可能不仅仅是由于药物蓄积的增加，还可能是因为激活了多条凋亡途径。(C)2009爱思唯尔爱尔兰有限公司。保留所有权利。
Doxorubicin (Dox) is a commonly used drug to treat various types of cancers. Previously, we demonstrated that coupling Dox to cell-penetrating peptides (CPPs) represent a valuable strategy to overcome drug resistance in MDA-MB 231 breast cancer cells. in the present study, we evaluated the properties of these Dox conjugates (Dox-CPPs) in terms of apoptosis induction. Dox-CPPs were found to induce apoptotic death in MDA-MB 231 cells at a lower dose than that needed for unconjugated Dox. Cell death induction was associated with Bax oligomerisation, release of cytochrome c, caspase activation, chromatin condensation and internucleosomal degradation. However, whereas Bcl-2 overexpression was very potent in inhibiting apoptosis triggered by Dox, this anti-apoptotic protein was largely inefficient in preventing Dox-CPPs-induced apoptosis. These observations suggest that mitochondrial disruption is the main event in Dox-induced apoptotic signaling but that Dox-CPPs are probably able to trigger additional apoptotic pathways independent of mitochondrial events. Thus, the higher efficacy of Dox conjugated to CCPs in apoptosis induction might not be due exclusively to increased drug accumulation but also to the activation of multiple apoptotic pathways. (C) 2009 Elsevier Ireland Ltd. All rights reserved.