Breast cancer resistance protein directly confers SN-38 resistance of lung cancer cells.
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.
Kawabata
S
S
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, 852-8501, Japan.
Oka
M
M
Shiozawa
K
K
Tsukamoto
K
K
Nakatomi
K
K
Soda
H
H
Fukuda
M
M
Ikegami
Y
Y
Sugahara
K
K
Yamada
Y
Y
Kamihira
S
S
Doyle
L A
LA
Ross
D D
DD
Kohno
S
S
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D015152:Blotting, Northern; D018938:Caco-2 Cells; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D016373:DNA, Antisense / Q000235:genetics / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D016373:DNA, Antisense; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000077146:Irinotecan; D002166:Camptothecin