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- Title
Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer.
- Authors
HAIYANG CHEN; KAZUHIKO SHIEN; KEN SUZAWA; KAZUNORI TSUKUDA; SHUTA TOMIDA; HIROKI SATO; HIDEJIRO TORIGOE; MOTOTSUGU WATANABE; KEI NAMBA; HIROMASA YAMAMOTO; JUNICHI SOH; HIROAKI ASANO; SHINICHIRO MIYOSHI; SHINICHI TOYOOKA
- Abstract
Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxel-resistant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.
- Subjects
CANCER treatment; NON-small-cell lung carcinoma; DOCETAXEL; EPIDERMAL growth factor receptors; COMBINATION drug therapy; DRUG resistance
- Publication
Oncology Letters, 2017, Vol 14, Issue 4, p4349
- ISSN
1792-1074
- Publication type
Article
- DOI
10.3892/ol.2017.6678