Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non‑small cell lung cancer

Chen,Haiyang; Shien,Kazuhiko; Suzawa,Ken; Tsukuda,Kazunori; Tomida,Shuta; Sato,Hiroki; Torigoe,Hidejiro; Watanabe,Mototsugu; Namba,Kei; Yamamoto,Hiromasa; Soh,Junichi; Asano,Hiroaki; Miyoshi,Shinichiro; Toyooka,Shinichi

doi:10.3892/ol.2017.6678

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
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Affiliations: Department of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan, Department of Bioinformatics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan
Published online on: July 26, 2017 https://doi.org/10.3892/ol.2017.6678
Pages: 4349-4354

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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.

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1	Wu L, Chang W, Zhao J, Yu Y, Tan X, Su T, Zhao L, Huang S, Liu S and Cao G: Development of autoantibody signatures as novel diagnostic biomarkers of non-small cell lung cancer. Clin Cancer Res. 16:3760–3768. 2010.PubMed/NCBI
2	Rigas JR and Kelly K: Current treatment paradigms for locally advanced non-small cell lung cancer. J Thorac Oncol. 2:(Suppl 2). S77–S85. 2007. View Article : Google Scholar : PubMed/NCBI
3	Choy H, Pyo H, Kim JS and MacRae R: Role of taxanes in the combined modality treatment of patients with locally advanced non-small cell lung cancer. Expert Opin Pharmacother. 2:963–974. 2001. View Article : Google Scholar : PubMed/NCBI
4	Wakelee H, Ramalingam S and Belani CP: Docetaxel in advanced non-small cell lung cancer. Expert Rev Anticancer Ther. 5:13–24. 2005. View Article : Google Scholar : PubMed/NCBI
5	Stinchcombe TE: Recent advances in the treatment of non-small cell and small cell lung cancer. F1000Prime Rep. 6:1172014. View Article : Google Scholar : PubMed/NCBI
6	Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, et al: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): A multicentre, double-blind, randomised phase 3 trial. Lancet. 384:665–673. 2014. View Article : Google Scholar : PubMed/NCBI
7	Yoh K, Hosomi Y, Kasahara K, Yamada K, Takahashi T, Yamamoto N, Nishio M, Ohe Y, Koue T, Nakamura T, et al: A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs. placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy. Lung Cancer. 99:186–193. 2016. View Article : Google Scholar : PubMed/NCBI
8	Lage H: An overview of cancer multidrug resistance: A still unsolved problem. Cell Mol Life Sci. 65:3145–3167. 2008. View Article : Google Scholar : PubMed/NCBI
9	Myer MS, Joone G, Chasen MR and van Rensburg CE: The chemosensitizing potential of GF120918 is independent of the magnitude of P-glycoprotein-mediated resistance to conventional chemotherapeutic agents in a small cell lung cancer line. Oncol Rep. 6:217–218. 1999.PubMed/NCBI
10	Galletti E, Magnani M, Renzulli ML and Botta M: Paclitaxel and docetaxel resistance: Molecular mechanisms and development of new generation taxanes. ChemMedChem. 2:920–942. 2007. View Article : Google Scholar : PubMed/NCBI
11	Orr GA, Verdier-Pinard P, McDaid H and Horwitz SB: Mechanisms of Taxol resistance related to microtubules. Oncogene. 22:7280–7295. 2003. View Article : Google Scholar : PubMed/NCBI
12	Luqmani YA: Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract. 14:(Suppl 1). S35–S48. 2005. View Article : Google Scholar
13	Gottesman MM and Ambudkar SV: Overview: ABC transporters and human disease. J Bioenerg Biomembr. 33:453–458. 2001. View Article : Google Scholar : PubMed/NCBI
14	Sarkadi B, Homolya L, Szakács G and Váradi A: Human multidrug resistance ABCB and ABCG transporters: Participation in a chemoimmunity defense system. Physiol Rev. 86:1179–1236. 2006. View Article : Google Scholar : PubMed/NCBI
15	Higgins CF: Multiple molecular mechanisms for multidrug resistance transporters. Nature. 446:749–757. 2007. View Article : Google Scholar : PubMed/NCBI
16	Sharom FJ: ABC multidrug transporters: Structure, function and role in chemoresistance. Pharmacogenomics. 9:105–127. 2008. View Article : Google Scholar : PubMed/NCBI
17	Li Y, Yuan H, Yang K, Xu W, Tang W and Li X: The structure and functions of P-glycoprotein. Curr Med Chem. 17:786–800. 2010. View Article : Google Scholar : PubMed/NCBI
18	Szakács G, Váradi A, Ozvegy-Laczka C and Sarkadi B: The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 13:379–393. 2008. View Article : Google Scholar : PubMed/NCBI
19	Palmeira A, Sousa E, Vasconcelos MH and Pinto MM: Three decades of P-gp inhibitors: Skimming through several generations and scaffolds. Curr Med Chem. 19:1946–2025. 2012. View Article : Google Scholar : PubMed/NCBI
20	Wu CP, Calcagno AM and Ambudkar SV: Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: Evaluation of current strategies. Curr Mol Pharmacol. 1:93–105. 2008. View Article : Google Scholar : PubMed/NCBI
21	Hubensack M, Müller C, Höcherl P, Fellner S, Spruss T, Bernhardt G and Buschauer A: Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J Cancer Res Clin Oncol. 134:597–607. 2008. View Article : Google Scholar : PubMed/NCBI
22	Kajiyama H, Shibata K, Terauchi M, Yamashita M, Ino K, Nawa A and Kikkawa F: Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. Int J Oncol. 31:277–283. 2007.PubMed/NCBI
23	Min C, Eddy SF, Sherr DH and Sonenshein GE: NF-kappaB and epithelial to mesenchymal transition of cancer. J Cell Biochem. 104:733–744. 2008. View Article : Google Scholar : PubMed/NCBI
24	Sabbah M, Emami S, Redeuilh G, Julien S, Prévost G, Zimber A, Ouelaa R, Bracke M, De Wever O and Gespach C: Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist Updat. 11:123–151. 2008. View Article : Google Scholar : PubMed/NCBI
25	Ren J, Chen Y, Song H, Chen L and Wang R: Inhibition of ZEB1 reverses EMT and chemoresistance in docetaxel-resistant human lung adenocarcinoma cell line. J Cell Biochem. 114:1395–1403. 2013. View Article : Google Scholar : PubMed/NCBI
26	Wu C and Alman BA: Side population cells in human cancers. Cancer Lett. 268:1–9. 2008. View Article : Google Scholar : PubMed/NCBI
27	Sugano T, Seike M, Noro R, Soeno C, Chiba M, Zou F, Nakamichi S, Nishijima N, Matsumoto M, Miyanaga A, et al: Inhibition of ABCB1 overcomes cancer stem cell-like properties and acquired resistance to MET inhibitors in non-small cell lung cancer. Mol Cancer Ther. 14:2433–2440. 2015. View Article : Google Scholar : PubMed/NCBI
28	O'Flaherty JD, Barr M, Fennell D, Richard D, Reynolds J, O'Leary J and O'Byrne K: The cancer stem-cell hypothesis: Its emerging role in lung cancer biology and its relevance for future therapy. J Thorac Oncol. 7:1880–1890. 2012. View Article : Google Scholar : PubMed/NCBI
29	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
30	Berns A: Stem cells for lung cancer? Cell. 121:811–813. 2005. View Article : Google Scholar : PubMed/NCBI
31	Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, Wang H, Liu Z, Su Y, Stass SA and Katz RL: Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res. 7:330–338. 2009. View Article : Google Scholar : PubMed/NCBI
32	Shien K, Toyooka S, Yamamoto H, Soh J, Jida M, Thu KL, Hashida S, Maki Y, Ichihara E, Asano H, et al: Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res. 73:3051–3061. 2013. View Article : Google Scholar : PubMed/NCBI
33	Wang YJ, Zhang YK, Kathawala RJ and Chen ZS: Repositioning of tyrosine kinase inhibitors as antagonists of ATP-binding cassette transporters in anticancer drug resistance. Cancers (Basel). 6:1925–1952. 2014. View Article : Google Scholar : PubMed/NCBI
34	Krishna R and Mayer LD: Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci. 11:265–283. 2000. View Article : Google Scholar : PubMed/NCBI
35	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
36	Scheel C and Weinberg RA: Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells? Int J Cancer. 129:2310–2314. 2011. View Article : Google Scholar : PubMed/NCBI
37	Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C, et al: Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69:4116–4124. 2009. View Article : Google Scholar : PubMed/NCBI
38	Gal A, Sjöblom T, Fedorova L, Imreh S, Beug H and Moustakas A: Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene. 27:1218–1230. 2008. View Article : Google Scholar : PubMed/NCBI
39	Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, et al: The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 133:704–715. 2008. View Article : Google Scholar : PubMed/NCBI
40	Dean M: ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 14:3–9. 2009. View Article : Google Scholar : PubMed/NCBI
41	Resetkova E, Reis-Filho JS, Jain RK, Mehta R, Thorat MA, Nakshatri H and Badve S: Prognostic impact of ALDH1 in breast cancer: A story of stem cells and tumor microenvironment. Breast Cancer Res Treat. 123:97–108. 2010. View Article : Google Scholar : PubMed/NCBI
42	Holohan C, Van Schaeybroeck S, Longley DB and Johnston PG: Cancer drug resistance: An evolving paradigm. Nat Rev Cancer. 13:714–726. 2013. View Article : Google Scholar : PubMed/NCBI
43	Mizuuchi H, Suda K, Sato K, Tomida S, Fujita Y, Kobayashi Y, Maehara Y, Sekido Y, Nishio K and Mitsudomi T: Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib. PLoS One. 10:e01239012015. View Article : Google Scholar : PubMed/NCBI
44	Goldman B: Multidrug resistance: Can new drugs help chemotherapy score against cancer? J Natl Cancer Inst. 95:255–257. 2003. View Article : Google Scholar : PubMed/NCBI
45	Mayur YC, Peters GJ, Prasad VV, Lemo C and Sathish NK: Design of new drug molecules to be used in reversing multidrug resistance in cancer cells. Curr Cancer Drug Targets. 9:298–306. 2009. View Article : Google Scholar : PubMed/NCBI