Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer
Abstract Background Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) in...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-08-01
|
| Series: | Thoracic Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/1759-7714.14527 |
| _version_ | 1818507733622587392 |
|---|---|
| author | Miwako Omori Rintaro Noro Masahiro Seike Kuniko Matsuda Mariko Hirao Aya Fukuizumi Natsuki Takano Akihiko Miyanaga Akihiko Gemma |
| author_facet | Miwako Omori Rintaro Noro Masahiro Seike Kuniko Matsuda Mariko Hirao Aya Fukuizumi Natsuki Takano Akihiko Miyanaga Akihiko Gemma |
| author_sort | Miwako Omori |
| collection | DOAJ |
| description | Abstract Background Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) inhibitors in SCLCs. Methods To identify key factors in the chemoresistance of SCLCs, we established four cell lines resistant to etoposide or an active metabolite of irinotecan, SN‐38, from SCLC cell lines and evaluated RNA profiles using parental and newly established cell lines. Results We found that the drug efflux protein, ATP‐binding cassette sub‐family B member 1 (ABCB1), was associated with resistance to etoposide, and ATP‐binding cassette sub‐family G member 2 (ABCG2) was associated with resistance to SN‐38 by RNA sequencing. The inhibition of ABCB1 or ABCG2 in each resistant cell line induced synergistic apoptotic activity and promoted drug sensitivity in resistant SCLC cells. The ABC transporter inhibitors, elacridar and tariquidar, restored sensitivity to etoposide or SN‐38 in in vitro and in vivo studies, and promoted apoptotic activity and G2‐M arrest in resistant SCLC cells. Conclusions ABC transporter inhibitors may be a promising therapeutic strategy for the purpose of overcoming resistance to topoisomerase inhibitors in patients with SCLC. |
| first_indexed | 2024-12-10T22:22:07Z |
| format | Article |
| id | doaj.art-67ccadb8f9304be1b1ff18d17e4b8dec |
| institution | Directory Open Access Journal |
| issn | 1759-7706 1759-7714 |
| language | English |
| last_indexed | 2024-12-10T22:22:07Z |
| publishDate | 2022-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Thoracic Cancer |
| spelling | doaj.art-67ccadb8f9304be1b1ff18d17e4b8dec2022-12-22T01:31:17ZengWileyThoracic Cancer1759-77061759-77142022-08-0113152142215110.1111/1759-7714.14527Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancerMiwako Omori0Rintaro Noro1Masahiro Seike2Kuniko Matsuda3Mariko Hirao4Aya Fukuizumi5Natsuki Takano6Akihiko Miyanaga7Akihiko Gemma8Department of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanDepartment of Pulmonary Medicine and Oncology Graduate School of Medicine, Nippon Medical School Tokyo JapanAbstract Background Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) inhibitors in SCLCs. Methods To identify key factors in the chemoresistance of SCLCs, we established four cell lines resistant to etoposide or an active metabolite of irinotecan, SN‐38, from SCLC cell lines and evaluated RNA profiles using parental and newly established cell lines. Results We found that the drug efflux protein, ATP‐binding cassette sub‐family B member 1 (ABCB1), was associated with resistance to etoposide, and ATP‐binding cassette sub‐family G member 2 (ABCG2) was associated with resistance to SN‐38 by RNA sequencing. The inhibition of ABCB1 or ABCG2 in each resistant cell line induced synergistic apoptotic activity and promoted drug sensitivity in resistant SCLC cells. The ABC transporter inhibitors, elacridar and tariquidar, restored sensitivity to etoposide or SN‐38 in in vitro and in vivo studies, and promoted apoptotic activity and G2‐M arrest in resistant SCLC cells. Conclusions ABC transporter inhibitors may be a promising therapeutic strategy for the purpose of overcoming resistance to topoisomerase inhibitors in patients with SCLC.https://doi.org/10.1111/1759-7714.14527ATP‐binding cassette transportersdrug resistancesmall cell lung cancertopoisomerase I inhibitortopoisomerase II inhibitor |
| spellingShingle | Miwako Omori Rintaro Noro Masahiro Seike Kuniko Matsuda Mariko Hirao Aya Fukuizumi Natsuki Takano Akihiko Miyanaga Akihiko Gemma Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer Thoracic Cancer ATP‐binding cassette transporters drug resistance small cell lung cancer topoisomerase I inhibitor topoisomerase II inhibitor |
| title | Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer |
| title_full | Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer |
| title_fullStr | Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer |
| title_full_unstemmed | Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer |
| title_short | Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer |
| title_sort | inhibitors of abcb1 and abcg2 overcame resistance to topoisomerase inhibitors in small cell lung cancer |
| topic | ATP‐binding cassette transporters drug resistance small cell lung cancer topoisomerase I inhibitor topoisomerase II inhibitor |
| url | https://doi.org/10.1111/1759-7714.14527 |
| work_keys_str_mv | AT miwakoomori inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT rintaronoro inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT masahiroseike inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT kunikomatsuda inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT marikohirao inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT ayafukuizumi inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT natsukitakano inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT akihikomiyanaga inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer AT akihikogemma inhibitorsofabcb1andabcg2overcameresistancetotopoisomeraseinhibitorsinsmallcelllungcancer |