Li Yun-Tian, Qian Xiao-Jun, Yu Yan, Li Zhen-Hua, Wu Rui-Yan, Ji Jiao, Jiao Lin, Li Xuan, Kong Peng-Fei, Chen Wen-Dan, Feng Gong-Kan, Deng Rong, Zhu Xiao-Feng
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou, China.
Department of Oncology, Anhui Provincial Hospital, Affiliated to Anhui Medical University, Hefei, China.
Oncotarget. 2015 Jul 10;6(19):17491-500. doi: 10.18632/oncotarget.3959.
The combination of time and order-dependent chemotherapeutic strategies has demonstrated enhanced efficacy in killing cancer cells while minimizing adverse effects. However, the precise mechanism remains elusive. Our results showed that pre-treatment of MCF-7 and MDA-MB-468 cells with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or lapatinib significantly enhanced the cytotoxic effects of DNA-damaging agents compared to coadministration of the EGFR inhibitor and DNA-damaging agent. Sequential application of erlotinib and doxorubicin increased activated caspase-8 by promoting pro-caspase-8 homodimerization and autocatalytical cleavage, whereas coadministration did not. We found that EGFR inhibitors promoted pro-caspase-8 homodimerization by inhibiting ERK pathway signaling, while doxorubicin promoted it. Our data highlight that ERK has the potential to inhibit the formation of pro-caspase-8 homodimers by phosphorylating pro-caspase-8 at S387. In conclusion, the pretreatment of EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging agents. Our findings provide rationale for novel strategies for the implementation of combined targeted and cytotoxic chemotherapy within a new framework of time and order-dependent therapy.
时间和顺序依赖性化疗策略的联合应用已证明在杀死癌细胞的同时将副作用降至最低方面具有更高的疗效。然而，确切机制仍不清楚。我们的结果表明，与表皮生长因子受体（EGFR）酪氨酸激酶抑制剂厄洛替尼或拉帕替尼联合使用DNA损伤剂相比，先用EGFR酪氨酸激酶抑制剂预处理MCF-7和MDA-MB-468细胞可显著增强DNA损伤剂的细胞毒性作用。厄洛替尼和阿霉素的序贯应用通过促进前半胱天冬酶-8同型二聚化和自催化裂解增加了活化的半胱天冬酶-8，而联合使用则没有。我们发现，EGFR抑制剂通过抑制ERK途径信号传导促进前半胱天冬酶-8同型二聚化，而阿霉素也有此作用。我们的数据表明，ERK有可能通过在S387位点磷酸化前半胱天冬酶-8来抑制其同型二聚体的形成。总之，EGFR酪氨酸激酶抑制剂的预处理促进了前半胱天冬酶-8的二聚化，从而使癌细胞对DNA损伤剂敏感。我们的研究结果为在新的时间和顺序依赖性治疗框架内实施联合靶向和细胞毒性化疗的新策略提供了理论依据。
