Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner
Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner
复制标题
DOI：
10.1016/j.bbrc.2005.12.039
复制
发表时间：
2006-02-10
影响因子：
3.1
通讯作者：
Kohno, M
中科院分区：
文献类型：
--
作者：
Fujiwara, Y;Kawada, K;Kohno, M
PI3激酶/Akt通路的组成性激活与大量人类肿瘤细胞的肿瘤表型相关。由于PI3激酶/Akt通路的抗凋亡作用已被证实。我们已经研究了特异性阻断该通路是否通过增强凋亡细胞死亡，使肿瘤细胞对dna损伤剂诱导的细胞毒性敏感。虽然PI3激酶抑制剂LY294002本身不诱导凋亡细胞死亡，但LY294002选择性地显著增强了阿霉素诱导凋亡的效果：这种增强的细胞死亡仅在PI3激酶/Akt通路组成性激活的肿瘤细胞中检测到，并且完全依赖于功能性p53通路。这些结果表明，PI3激酶/Akt通路抑制剂和阿霉素的联合治疗为PI3激酶/Akt通路组成性激活和p53通路功能性激活的肿瘤细胞提供了一种有效的化疗策略。(c) 2005爱思唯尔公司版权所有。
Constitutive activation of the PI3 kinase/Akt pathway is associated with the neoplastic phenotype of a large number of human tumor cells. As the anti-apoptotic role of the PI3 kinase/Akt pathway has been established. we have examined whether specific blockade of this pathway sensitizes tumor cells to DNA-damaging agent-induced cytotoxicity by enhancing apoptotic cell death. Although a PI3 kinase inhibitor, LY294002, by itself does not induce apoptotic cell death, LY294002 selectively and markedly enhances the apoptosis-inducing efficacy of doxorubicin: such an enhanced cell death is only detected in tumor cells in which the PI3 kinase/Akt pathway is constitutively activated, and it is totally dependent on the functional p53 pathway. These results suggest that the combination of a PI3 kinase/Akt pathway inhibitor and doxorubicin provides an efficient chemotherapeutic strategy for the treatment of tumour cells in which the PI3 kinase/Akt pathway is constitutively activated and the p53 pathway is functional. (c) 2005 Elsevier Inc. All rights reserved.