Drug-induced
interstitial lung disease (ILD), particularly
pulmonary fibrosis, is of serious clinical concern.
Gefitinib, a
tyrosine kinase inhibitor of the
epidermal growth factor receptor (EGFR), is beneficial as a drug for treating
non-small cell lung cancer; however, this drug induces ILD and the molecular mechanisms underpinning this condition remain unclear. We recently reported that expression of
heat shock protein 70 (HSP70) protects against
bleomycin-induced
pulmonary fibrosis, an animal model of
pulmonary fibrosis. In this study, we have examined the effects of drugs known to induce ILD clinically on the expression of HSP70 in cultured lung epithelial cells and have found that
gefitinib has a suppressive effect. Results of a
luciferase reporter assay, pulse-labelling analysis of
protein and experiments using an inhibitor of translation or transcription suggest that
gefitinib suppresses the expression of HSP70 at the level of translation. Furthermore, the results of experiments with
siRNA for Dicer1, an
enzyme responsible for synthesis of
microRNA, and real-time RT-PCR analysis suggest that some
microRNAs are involved in the
gefitinib-induced translational inhibition of HSP70. Mutations in the EGFR affect the concentration of
gefitinib required for suppressing the expression of HSP70. These results suggest that
gefitinib suppresses the translation of HSP70 through an EGFR- and
microRNA-mediated mechanism. In vivo, while
oral administration of
gefitinib suppressed the pulmonary expression of HSP70 and exacerbated
bleomycin-induced
pulmonary fibrosis in wild-type mice, these effects were not as distinct in transgenic mice expressing HSP70. Furthermore, oral co-administration of
geranylgeranylacetone (GGA), an inducer of HSP70, suppressed
gefitinib-induced exacerbation of
bleomycin-induced
pulmonary fibrosis. Taken together, these findings suggest that
gefitinib-induced exacerbation of
bleomycin-induced
pulmonary fibrosis is mediated by suppression of pulmonary expression of HSP70 and that an inducer of HSP70 expression, such as GGA, may be therapeutically beneficial for the treatment of
gefitinib-induced
pulmonary fibrosis.