Breast Cancer Resistance Protein Directly Confers SN-38 Resistance of Lung Cancer Cells

Authors: Kawabata S.¹; Oka M.^{1, 3}; Shiozawa K.¹; Tsukamoto K.^{1, 4}; Nakatomi K.¹; Soda H.^{1, 2}; Fukuda M.¹; Ikegami Y.⁵; Sugahara K.²; Yamada Y.²; Kamihira S.²; Doyle L.A.⁶; Ross D.D.^{6, 7}; Kohno S.^{1, 3}

Source: Biochemical and Biophysical Research Communications, Volume 280, Number 5, February 2001 , pp. 1216-1223(8)

Publisher: Academic Press

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Abstract:

Breast cancer resistance protein (BCRP), an ABC half-transporter, is overexpressed in cancer cell lines selected with doxorubicin/verapamil, topotecan, or mitoxantrone. BCRP-overexpressing cells show cross-resistance to camptothecin derivatives such as irinotecan, SN-38 (the active metabolite of irinotecan), and topotecan. To test whether BCRP confers SN-38 resistance, we selected two SN-38 resistant sublines from PC-6 human small-cell lung cancer cells by SN-38, and then characterized these cells. Compared to PC-6 cells, the resistant sublines PC-6/SN2-5 and PC-6/SN2-5H were approximately 18- and 34-fold resistant, respectively. The intracellular SN-38 accumulation was reduced in the sublines, and BCRP mRNA was overexpressed in proportion to the degree of SN-38 resistance. These findings suggest that BCRP confers SN-38 resistance in the sublines. To confirm this hypothesis, PC-6/SN2-5 cells were transfected with antisense oligonucleotides complementary to portions of BCRP mRNA. The antisense oligonucleotides significantly suppressed BCRP mRNA expression, and enhanced SN-38 sensitivity in the subline. These data indicate that BCRP is directly involved with SN-38 resistance, by efflux transport of SN-38. Copyright 2001 Academic Press.

Keywords: ABC transporter; half transporter; antisense oligonucleotide; drug resistance; multidrug resistance; lung cancer; topoisomerase I inhibitor

Language: English

Document Type: Research article

Affiliations: 1: Second Department of Internal Medicine 2: Second Department of Internal Medicine, Department of Laboratory Medicine, Nagasaki University School of Medicine, Nagasaki, 852-8501, Japan 3: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Medical Sciences, Nagasaki, 852-8523, Japan 4: Department of Pharmacotherapeutics, Nagasaki University Graduate School of Pharmaceutical Science, Nagasaki, 852-8521, Japan 5: Department of Drug Metabolism and Disposition, Meiji Pharmaceutical University, Kiyose, Tokyo, 204-8588, Japan 6: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, 21201 7: Department of Veterans Affairs, Baltimore Veterans Medical Center, Baltimore, Maryland, 21201

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