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Int J Oncol. 2012 Jan;40(1):194-202. doi: 10.3892/ijo.2011.1187. Epub 2011 Sep 5.

Treatment with the Chk1 inhibitor Gö6976 enhances cisplatin cytotoxicity in SCLC cells.

Author information

1
Institute for Cancer Studies, Sheffield University Medical School, Beech Hill Road, Sheffield S10 2RX, UK. ruth.h.thompson@dartmouth.edu

Abstract

Acquired chemoresistance is a major obstacle in successful treatment of small cell lung cancer (SCLC). DNA damage responses can potentially contribute to resistance by halting the cell cycle following exposure to therapeutic agents, thereby facilitating repair of drug-induced lesions and protecting tumour cells from death. The Chk1 protein kinase is a key regulator in this response. We analysed the status of cell cycle checkpoint proteins and the effects of the Chk1 inhibitor Gö6976 on cisplatin toxicity in SCLC cell lines. IC50s for cisplatin were determined using the MTT assay in six SCLC cell lines. Effects on cell cycle distribution and apoptosis were determined by flow cytometry and caspase 3 activation in the presence or absence of the Chk1 inhibitor Gö6976. The activation of checkpoint proteins was determined by Western blotting. Cell lines were divided into chemosensitive and chemoresistant groups on the basis of our results. While checkpoint responses were detected in these cell lines through Western blotting, some of these responses were delayed or weaker than those seen in other cell types in response to DNA damage and replication stress. Gö6976 significantly (p<0.05) enhanced the levels of apoptosis seen in response to a clinically relevant dose of cisplatin (<6 µM) and decreased drug-induced G2 arrest in chemosensitive cells. Our data suggest a role for Chk1 in chemoresistance of SCLC cells and a potential approach to improve initial response of SCLC to cisplatin therapy.

PMID:
21894433
DOI:
10.3892/ijo.2011.1187
[Indexed for MEDLINE]

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