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.
Highlights
Gefitinib (ZD1839, Iressa) is a widely used treatment for non-small cell lung cancer (NSCLC) patients who harbor the EGFR mutation
Exosomes isolated from doxorubicin or doxorubicin combined with heat-stress-treated MCF-7 cells significantly inhibited MCF-7 cell proliferation and triggered MCF-7 cell apoptosis [28]. This is consistent with our work, where we demonstrated that exosomes derived from PC9 cells treated with either gefitinib or cisplatin could modestly inhibit proliferation of co-cultured PC9 cells
We have previously reported that up-regulation of autophagy contributed to the antagonistic effects between gefitinib and cisplatin [19]; in the present study, we investigated whether up-regulated autophagy was mediated by exosome secretion
Summary
Gefitinib (ZD1839, Iressa) is a widely used treatment for NSCLC patients who harbor the EGFR mutation. Several randomized phase III clinical trials have demonstrated that the simultaneous administration of gefitinib or erlotinib with platinum-based doublet chemotherapy did not improve overall survival (OS) when compared to chemotherapy alone [1,2,3,4]. Adverse events occurred mainly in the groups that were administered the drug combination, most of the adverse events resulted from the known toxicities of the chemotherapy agents [1,2,3,4]. Previous reports indicate that sequential administration of chemotherapy followed by TKIs results in progression-free survival (PFS) when compared to chemotherapy alone [5, 6]. In the FASTACT [5] and FASTACT-2 [9] clinical trials, an interaction between TKIs and chemotherapy was observed even though chemotherapy www.impactjournals.com/oncotarget was administered at the end of erlotinib treatment. An alternate mechanism may be responsible for the antagonistic effect between chemotherapy and EGFRTKIs
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