Exosomes derived from gefitinib-treated EGFR-mutant lung cancer cells alter cisplatin sensitivity via up-regulating autophagy.
Exosomes derived from gefitinib-treated EGFR-mutant lung cancer cells alter cisplatin sensitivity via up-regulating autophagy.
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来自吉非替尼治疗的 EGFR 突变肺癌细胞的外泌体通过上调自噬改变顺铂敏感性
DOI：
10.18632/oncotarget.8358
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Sun GP
中科院分区：
文献类型：
--
作者：
Li XQ;Liu JT;Fan LL;Liu Y;Cheng L;Wang F;Yu HQ;Gao J;Wei W;Wang H;Sun GP
一些临床试验表明，酪氨酸激酶抑制剂(TKI，如吉非替尼或厄洛替尼)与化疗药物同时应用，未能提高晚期非小细胞肺癌(NSCLC)患者的总体生存率。然而，这种拮抗效应背后的确切机制仍不清楚。在本研究中，我们研究了外切体在同时给予化疗和TKIs的拮抗作用中的作用。经Gefitinib处理的PC9细胞来源的外切体(Exo-GF)可降低顺铂的抗肿瘤作用，而经顺铂处理的PC9细胞来源的Exo-DDP对Gefitinib的抗肿瘤作用无明显影响。此外，当顺铂和吉非替尼合用时，GW4869抑制外切体的分泌可产生轻微的协同作用。此外，Exo-GF与顺铂共同孵育可增加自噬活性，减少细胞凋亡，表现为上调Lc3-II和Bcl2蛋白水平，下调p62和Bax蛋白水平。因此，吉非替尼和顺铂的拮抗作用主要归因于Exo-GF导致自噬上调和顺铂耐药性增加。这些结果表明，当TKI与化疗药物联合应用时，抑制外切体的分泌可能是克服拮抗作用的一种有用的策略。在化疗前，引入一段洗脱期以完全消除TKI相关的外切体，可能是一种更好的化疗和TKI治疗方法。
Several clinical trials indicate that concurrent administration of tyrosine kinase inhibitors (TKIs, such as gefitinib or erlotinib) with chemotherapy agents fails to improve overall survival in advanced non-small cell lung cancer (NSCLC) patients. However, the precise mechanisms underlying the antagonistic effects remain unclear. In the present study, we investigated the role of exosomes in the antagonistic effects of concurrent administration of chemotherapy and TKIs. Exosomes derived from gefitinib-treated PC9 cells (Exo-GF) decreased the antitumor effects of cisplatin, while exosomes derived from cisplatin-treated PC9 cells (Exo-DDP) did not significantly affect the antitumor effects of gefitinib. Additionally, inhibition of exosome secretion by GW4869 resulted in a modest synergistic effect when cisplatin and gefitinib were co-administered. Furthermore, Exo-GF co-incubation with cisplatin increased autophagic activity and reduced apoptosis, as demonstrated by an upregulation of LC3-II and Bcl-2 protein levels and downregulation of p62 and Bax protein levels. Thus, the antagonistic effects of gefitinib and cisplatin were mainly attributed to Exo-GF, which resulted in upregulated autophagy and increased cisplatin resistance. These results suggest that inhibition of exosome secretion may be a helpful strategy to overcome the antagonistic effects when TKIs and chemotherapeutic agents are co-administered. Before administering chemotherapy, introducing a washout period to completely eliminate TKI-related exosomes, may be a better procedure for administering chemotherapy and TKIs.
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45.3
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