Inhibitors of ABCB1 and ABCG2 overcame resistance to topoisomerase inhibitors in small cell lung cancer

Abstract

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.

Keywords

• ATP‐binding cassette transporters
• drug resistance
• small cell lung cancer
• topoisomerase I inhibitor
• topoisomerase II inhibitor