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BCRP/ABCG2 levels account for the resistance to topoisomerase I inhibitors and reversal effects by gefitinib in non-small cell lung cancer

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Abstract

Purpose: Breast cancer resistance protein (BCRP) confers resistance against topoisomerase I inhibitors in cancer cells. Very recently, we reported that gefitinib reverses BCRP-mediated drug resistance by direct inhibition. However, it remains undetermined how much BCRP contributes to the resistance to topoisomerase I inhibitors in non-small cell lung cancer (NSCLC). The present study was designed to examine whether BCRP levels in NSCLC cells are correlated with the resistance to topoisomerase I inhibitors and the reversal effect by gefitinib. Methods: BCRP levels and its function were evaluated by Western blotting and flowcytometry, respectively. Gefitinib-insensitive NSCLC cells expressed various levels of BCRP, which were closely correlated not only with the IC50 values of SN-38 (r=0.874, P<0.05) and those of topotecan (r=0.968, P<0.001), but also with the reversal effects of 1 μM gefitinib on SN-38 resistance (r=0.956, P<0.001) and topotecan resistance (r=0.977, P=0.0001). Results: BCRP levels accounted for between 80 and 90% of the variation in the resistance to topoisomerase I inhibitors and the reversal effects by gefitinib. Also, gefitinib increased intracellular topotecan accumulation in proportion to the BCRP levels. Conclusions: These findings suggest that BCRP is the most important molecule responsible for topoisomerase I inhibitor resistance, and that the development of BCRP inhibitors is an effective approach for overcoming this resistance. In addition, the examination of BCRP levels in NSCLC tissues may identify an optimal patient population for treatment with topoisomerase I inhibitors alone or in combination with BCRP inhibitors.

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Abbreviations

ABC:

ATP-binding cassette

NSCLC:

Non-small cell lung cancer

BCRP:

Breast cancer resistance protein

EGFR:

Epidermal growth factor receptor

SN-38:

7-Ethyl-10-hydroxycamptothecin (the active metabolite of irinotecan)

MRP:

Multidrug resistance protein

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Authors and Affiliations

  1. Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan

    Seiji Nagashima, Hiroshi Soda, Takeshi Kitazaki, Ken Shiozawa, Yoichi Nakamura & Shigeru Kohno

  2. Division of Respiratory Diseases, Department of Medicine, Kawasaki Medical School, Okayama, Japan

    Mikio Oka & Minoru Fukuda

  3. GenoMembrane, Kanagawa, Japan

    Masaaki Takemura & Hikaru Yabuuchi

  4. Department of Pharmacotherapeutics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    Kazuhiro Tsukamoto

Authors
  1. Seiji Nagashima
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  2. Hiroshi Soda
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  3. Mikio Oka
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  4. Takeshi Kitazaki
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  5. Ken Shiozawa
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  6. Yoichi Nakamura
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  8. Hikaru Yabuuchi
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  9. Minoru Fukuda
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  11. Shigeru Kohno
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Corresponding author

Correspondence to Hiroshi Soda.

Additional information

S. Nagashima and H. Soda contributed equally to this study.

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Nagashima, S., Soda, H., Oka, M. et al. BCRP/ABCG2 levels account for the resistance to topoisomerase I inhibitors and reversal effects by gefitinib in non-small cell lung cancer. Cancer Chemother Pharmacol 58, 594–600 (2006). https://doi.org/10.1007/s00280-006-0212-y

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  • DOI: https://doi.org/10.1007/s00280-006-0212-y

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