title: Treatment with the Chk1 inhibitor Gö6976 enhances cisplatin cytotoxicity             in SCLC cells.
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.
authors: Institute for Cancer Studies, Sheffield University Medical School, Beech Hill Road, Sheffield S10 2RX, UK. ruth.h.thompson@dartmouth.edu
authors: Ruth
authors: R
authors: Thompson
authors: Mark
authors: M
authors: Meuth
authors: Penella
authors: P
authors: Woll
authors: Yong
authors: Y
authors: Zhu
authors: Sarah
authors: S
authors: Danson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D002227:Carbazoles; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; C081021:Go 6976; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002945:Cisplatin