title: Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells.
abstract: Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxy-campthothecin (SN-38) is an active metabolite of irinotecan. Gefitinib and imatinib are tyrosine kinase inhibitors which have clinical activities in several malignancies and they are also potent inhibitors of breast cancer resistance protein (BCRP) transporter, which confers the resistance of topoisomerase I inhibitors including SN-38 and topotecan. The cytotoxicity of SN-38, gefitinib and imatinib for the SN-38-resistant cells (SBC-3/SN-38) from human SCLC cells, SBC-3, was evaluated using AlamarBlue assay. The drug concentration required to inhibit the growth of tumor cells by 50% (IC50) for 96-h exposure was used to evaluate the cytotoxicity. BCRP expression was determined by Western blotting and immunofluorescence staining. Intracellular topotecan accumulation was evaluated by flow cytometry. No differences were observed in the IC50 values (mean +/- SD) of the tyrosine kinase inhibitors between the SBC-3 cells and the SBC-3/SN-38 cells: 15+/-1.6 and 12+/-2.8 microM of gefitinib, respectively; 15+/-0.51 and 14+/-3.9 microM of imatinib, respectively. The SBC-3/SN-38 was 9.5-fold more resistant to SN-38 than the parental SBC-3. The SBC-3/SN-38 restored sensitivity to SN-38 when combined with 8 microM gefitinib or 8 microM imatinib, even though the IC50 values of SN-38 combined with gefitinib or imatinib in the SBC-3 cells did not change. BCRP was equally overexpressed in the SBC-3/SN-38 with and without gefitinib or imatinib. In addition, the BCRP expression on the SBC-3/SN-38 cell membrane with and without gefitinib seemed to be equal. Gefitinib increased intracellular accumulation of topotecan in the SBC-3/SN-38 cells. Gefitinib or imatinib reversed SN-38-resistance in these SCLC cells, possibly due to intracellular accumulation of SN-38 without any change in BCRP quantity. Irinotecan with gefitinib or imatinib might be effective for SCLC refractory to irinotecan.
authors: Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan. ntakigaw@md.okayama-u.ac.jp
authors: Nagio
authors: N
authors: Takigawa
authors: Masami
authors: M
authors: Takeyama
authors: Toshiyuki
authors: T
authors: Kozuki
authors: Takuo
authors: T
authors: Shibayama
authors: Akiko
authors: A
authors: Hisamoto
authors: Katsuyuki
authors: K
authors: Kiura
authors: Atsuhiko
authors: A
authors: Tada
authors: Katsuyuki
authors: K
authors: Hotta
authors: Shigeki
authors: S
authors: Umemura
authors: Kadoaki
authors: K
authors: Ohashi
authors: Yoshiro
authors: Y
authors: Fujiwara
authors: Saburo
authors: S
authors: Takata
authors: Eiki
authors: E
authors: Ichihara
authors: Masahiro
authors: M
authors: Osawa
authors: Masahiro
authors: M
authors: Tabata
authors: Mitsune
authors: M
authors: Tanimoto
authors: Kiyoshi
authors: K
authors: Takahashi
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D011799:Quinazolines; D000077146:Irinotecan; D000068877:Imatinib Mesylate; D000077156:Gefitinib; D002166:Camptothecin