Role of ABCG2 as a biomarker for predicting resistance to CPT-11/SN-38 in lung cancer.
To examine the mechanism of resistance to 7-ethyl-10-hydroxycamptothecin (SN-38) in lung cancer, we continuously exposed the non-small-cell lung cancer (NSCLC) cell line NCI-H23 to SN-38 and selected the SN-38-resistant clone H23/SN-38. After 2 months of culturing in SN-38-free conditions, H23/SN-38 cells recovered their sensitivity to SN-38 and were subsequently established as the revertant H23/SN-38REV cell line. Because H23/SN-38 cells show cross resistance to certain anticancer drugs, such as topotecan, etoposide, doxorubicin and mitoxantrone, we examined the gene and protein expression levels of drug efflux transporters of the ATP-binding cassette (ABC) family. We found that both gene and protein expression of ABCG2/BCRP (ABCG2) in H23/SN-38 cells was increased compared with that in NCI-H23 cells and H23/SN-38REV cells. The cellular accumulation of topotecan in H23/SN-38 cells was decreased compared with that in NCI-H23 and H23/SN-38REV cells, and treatment with reserpine (an inhibitor of ABCG2) increased the cellular accumulation of topotecan in H23/SN-38 cells. Furthermore, treatment with reserpine also altered the sensitivity of H23/SN-38 cells to SN-38. These results indicate that the upregulation of ABCG2 was functional, and related to the resistance of H23/SN-38 cells to SN-38. Moreover, we found that gene expression levels of ABCG2 were significantly correlated with the concentration of SN-38 for 50% cell survival in 13 NSCLC cells (r=0.592, P<0.05). The present results indicate that the induction of ABCG2 by SN-38 does confer acquired resistance to CPT-11/SN-38, but the induction of ABCG2 and subsequent drug resistance are reversible. However, the expression level of ABCG2 may be a useful indicator of CPT-11/SN-38 activity in lung cancer.
Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Yuji
Y
Bessho
Tetsuya
T
Oguri
Hiroyuki
H
Achiwa
Hideki
H
Muramatsu
Hiroyoshi
H
Maeda
Takashi
T
Niimi
Shigeki
S
Sato
Ryuzo
R
Ueda
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000077146:Irinotecan; D002166:Camptothecin