The ratio of Bcl-2/Bim as a predictor of cisplatin response provides a rational combination of ABT-263 with cisplatin or radiation in small cell lung cancer

BACKGROUND: Cisplatin-based chemotherapy and radiotherapy are the most commonly used treatments for small cell lung cancer (SCLC). However, despise initially dramatic response, the response duration of SCLC patients is variable and resistance to chemo- and radio-therapy inevitably develops. OBJECTIVE: The aim of the study is to investigate the role of Bcl-2 family proteins in predicting SCLC sensitivity to cisplatin treatment, and to identify the potential sensitizer of cisplatin or ratiation treatment in SCLC. METHODS: We collected cisplatin sensitivity data from public available database, and evaluated its possible association with mRNA or protein expression of Bcl-2 family members in SCLC cell lines. RESULTS: The IC50 value of cisplatin was significantly correlated with the ratio of Bcl-2/Bim mRNA expression in 33 SCLC cell lines (P= 0.041) as well as the ratio of Bcl-2/Bim protein expression in 7 SCLC cell lines (P= 0.0252). Furthermore, a BH3-mimetic ABT-263 was found to be able to sensitize SCLC cells to cisplatin or radiation. The synergistic and additive antitumor activity of ABT-263 combined with cisplatin or radiation was associated with the enhanced apoptosis, which may be caused by the disruption of Bcl-2 binding to Bim by ABT-263. CONCLUSIONS: Our study indicates that the ratio of Bcl-2/Bim could be a SCLC response predictor to cisplatin, and ABT-263 addition could be an effective strategy to improve the activity of chemo- or radio-therapy in SCLC.