Comparison of autophagy inducibility in various tyrosine kinase inhibitors and their enhanced cytotoxicity via inhibition of autophagy in cancer cells in combined treatment with azithromycin.
Biochem Biophys Rep
; 22: 100750, 2020 Jul.
Article
en En
| MEDLINE
| ID: mdl-32195376
ABSTRACT
Tyrosine kinase inhibitors (TKIs) induce autophagy in many types of cancer cells. We previously reported that gefitinib (GEF) and imatinib (IMA) induce autophagy in epidermal growth factor receptor (EGFR) knock-out A549 and non-BCR-ABL-expressing leukemia cell lines, respectively. This evidence suggests that TKI-induced autophagy is independent of the original target molecules. The present study compared the autophagy-inducing abilities of various TKIs, regardless of their targets, by quantitative autophagy flux assay. We established stable clones expressing the GFP-LC3-mCherry-LC3ΔG plasmid in A549, PC-9, and CAL 27 cell lines and assessed autophagy inducibility by monitoring the fluorescent ratios of GFP-LC3 to mCherry-LC3ΔG using an IncuCyte live cell imaging system during exposure to TKIs viz; GEF, osimertinib (OSI), lapatinib (LAP), lenvatinib (LEN), sorafenib (SOR), IMA, dasatinib (DAS), and tivantinib (TIV). Among these TKIs, DAS, GEF, and SOR exhibited prominent autophagy induction in A549 and PC-9 cells. In CAL 27 cells, IMA, SOR, and LEN, but not GEF, TIV, or OSI, exhibited autophagy induction. In the presence of azithromycin (AZM), which showed an inhibitory effect on autophagy flux, TKIs with prominent autophagy inducibility exhibited enhanced cytotoxicity via non-apoptotic cell death relative to effects of TKI alone. Therefore, autophagy inducibility of TKIs differed in the context of cancer cells. However, once induced, they appeared to have cytoprotective functions. Thus, blocking TKI-induced autophagy with AZM may improve the therapeutic effect of TKIs in cancer cells.
Autophagy; Cancer; Macrolide antibiotics; Tyrosine kinase inhibitor; azithromycin, AZM; bafilomycin A1, BAF; dasatinib, DAS; gefitinib, GEF; imatinib, IMA; lapatinib, LAP; lenvatinib, LEN; osimertinib, OSI; receptor tyrosine kinase, RTK; sorafenib, SOR; tivantinib, TIV; tyrosine kinase inhibitors, TKIs
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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Biochem Biophys Rep
Año:
2020
Tipo del documento:
Article
País de afiliación:
Japón