Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells

Nagio Takigawa; Masami Takeyama; Toshiyuki Kozuki; Takuo Shibayama; Akiko Hisamoto; Katsuyuki Kiura; Atsuhiko Tada; Katsuyuki Hotta; Shigeki Umemura; Kadoaki Ohashi; Yoshiro Fujiwara; Saburo Takata; Eiki Ichihara; Masahiro Osawa; Masahiro Tabata; Mitsune Tanimoto; Kiyoshi Takahashi

doi:10.3892/or.17.5.983

Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells

Nagio Takigawa, Masami Takeyama, Toshiyuki Kozuki, Takuo Shibayama, Akiko Hisamoto, Katsuyuki Kiura, Atsuhiko Tada, Katsuyuki Hotta, Shigeki Umemura, Kadoaki Ohashi, Yoshiro Fujiwara, Saburo Takata, Eiki Ichihara, Masahiro Osawa, Masahiro Tabata, Mitsune Tanimoto, Kiyoshi Takahashi

University Hospital

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxycampthothecin (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 μM of gefitinib, respectively; 15±0.51 and 14±3.9 μM 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 μM gefitinib or 8 μM 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.

Original language	English
Pages (from-to)	983-987
Number of pages	5
Journal	Oncology reports
Volume	17
Issue number	5
DOIs	https://doi.org/10.3892/or.17.5.983
Publication status	Published - May 2007

Keywords

Gefitinib
Imatinib
Irinotecan
Small-cell lung cancer
Topotecan

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3892/or.17.5.983

Cite this

Takigawa, N., Takeyama, M., Kozuki, T., Shibayama, T., Hisamoto, A., Kiura, K., Tada, A., Hotta, K., Umemura, S., Ohashi, K., Fujiwara, Y., Takata, S., Ichihara, E., Osawa, M., Tabata, M., Tanimoto, M., & Takahashi, K. (2007). Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells. Oncology reports, 17(5), 983-987. https://doi.org/10.3892/or.17.5.983

Takigawa, N, Takeyama, M, Kozuki, T, Shibayama, T, Hisamoto, A, Kiura, K, Tada, A, Hotta, K, Umemura, S, Ohashi, K, Fujiwara, Y, Takata, S, Ichihara, E, Osawa, M, Tabata, M, Tanimoto, M & Takahashi, K 2007, 'Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells', Oncology reports, vol. 17, no. 5, pp. 983-987. https://doi.org/10.3892/or.17.5.983

@article{7adb7030a1ee43d2a6bafe43e57447b0,

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-hydroxycampthothecin (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 μM of gefitinib, respectively; 15±0.51 and 14±3.9 μM 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 μM gefitinib or 8 μM 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.",

keywords = "Gefitinib, Imatinib, Irinotecan, Small-cell lung cancer, Topotecan",

author = "Nagio Takigawa and Masami Takeyama and Toshiyuki Kozuki and Takuo Shibayama and Akiko Hisamoto and Katsuyuki Kiura and Atsuhiko Tada and Katsuyuki Hotta and Shigeki Umemura and Kadoaki Ohashi and Yoshiro Fujiwara and Saburo Takata and Eiki Ichihara and Masahiro Osawa and Masahiro Tabata and Mitsune Tanimoto and Kiyoshi Takahashi",

year = "2007",

month = may,

doi = "10.3892/or.17.5.983",

language = "English",

volume = "17",

pages = "983--987",

journal = "Oncology Reports",

issn = "1021-335X",

publisher = "Spandidos Publications",

number = "5",

}

TY - JOUR

T1 - Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells

AU - Takigawa, Nagio

AU - Takeyama, Masami

AU - Kozuki, Toshiyuki

AU - Shibayama, Takuo

AU - Hisamoto, Akiko

AU - Kiura, Katsuyuki

AU - Tada, Atsuhiko

AU - Hotta, Katsuyuki

AU - Umemura, Shigeki

AU - Ohashi, Kadoaki

AU - Fujiwara, Yoshiro

AU - Takata, Saburo

AU - Ichihara, Eiki

AU - Osawa, Masahiro

AU - Tabata, Masahiro

AU - Tanimoto, Mitsune

AU - Takahashi, Kiyoshi

PY - 2007/5

Y1 - 2007/5

N2 - Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxycampthothecin (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 μM of gefitinib, respectively; 15±0.51 and 14±3.9 μM 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 μM gefitinib or 8 μM 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.

AB - Irinotecan is one of the effective anticancer agents for small-cell lung cancer (SCLC) and 7-ethyl-10-hydroxycampthothecin (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 μM of gefitinib, respectively; 15±0.51 and 14±3.9 μM 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 μM gefitinib or 8 μM 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.

KW - Gefitinib

KW - Imatinib

KW - Irinotecan

KW - Small-cell lung cancer

KW - Topotecan

UR - http://www.scopus.com/inward/record.url?scp=34548553041&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548553041&partnerID=8YFLogxK

U2 - 10.3892/or.17.5.983

DO - 10.3892/or.17.5.983

M3 - Article

C2 - 17390033

AN - SCOPUS:34548553041

SN - 1021-335X

VL - 17

SP - 983

EP - 987

JO - Oncology Reports

JF - Oncology Reports

IS - 5

ER -

Combination of SN-38 with gefitinib or imatinib overcomes SN-38-resistant small-cell lung cancer cells

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this