title: Exosomes derived from gefitinib-treated EGFR-mutant lung cancer cells alter cisplatin sensitivity via up-regulating autophagy.
abstract: 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.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Xiao-Qiu
authors.initials: XQ
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.|Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Jia-Tao
authors.initials: JT
authors.lastname: Liu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Lu-Lu
authors.initials: LL
authors.lastname: Fan
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Han-Qing
authors.initials: HQ
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D055354:Exosomes / Q000187:drug effects*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D000077156:Gefitinib
keywords: autophagy; cisplatin; exosomes; gefitinib; lung cancer