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

• Published in: Biochemical and biophysical research communications 2001-02, Vol.280 (5), p.1216-1223
• Main Authors: Kawabata, Shigeru, Oka, Mikio, Shiozawa, Ken, Tsukamoto, Kazuhiro, Nakatomi, Katsumi, Soda, Hiroshi, Fukuda, Minoru, Ikegami, Yoji, Sugahara, Kazuyuki, Yamada, Yasuaki, Kamihira, Shimeru, Doyle, L.Austin, Ross, Douglas D., Kohno, Shigeru
• Format: Article
• Language: English
• Subjects: ABC transporter; Antineoplastic Agents, Phytogenic - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; antisense oligonucleotide; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; Blotting, Northern; Caco-2 Cells; Camptothecin - analogs & derivatives; Camptothecin - metabolism; Camptothecin - pharmacology; DNA, Antisense - genetics; DNA, Antisense - physiology; drug resistance; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; half transporter; Humans; lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; multidrug resistance; Neoplasm Proteins; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; topoisomerase I inhibitor; Transfection; Tumor Cells, Cultured - drug effects
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2001.4267

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.