title: Dysfunction of volume-sensitive chloride channels contributes to cisplatin resistance in human lung adenocarcinoma cells.
abstract: Cisplatin-based chemotherapy is the standard therapy used to treat non-small-cell lung cancer. However, its efficacy is largely limited due to the development of drug resistance. The exact mechanism in which cancer cells develop resistance to the drug is not yet fully understood. The purpose of the present study is to test the role of volume-sensitive Cl(-) channels in cisplatin resistance in human lung adenocarcinoma cells (A549 cells) using patch-clamp recording, cell volume measurement and apoptosis assay. The results showed that cisplatin treatment induced an apoptotic volume decrease (AVD) and activated a Cl(-) current that showed properties similar to the volume-sensitive outward rectifying (VSOR) Cl(-) current in wild-type A549 cells. Both the AVD process and VSOR Cl(-) current were blocked by the chloride channel blocker 4,4'-diisothiocyanostilbene-2,2' disulfonic acid. However, the A549/CDDP cells, a model of acquired cisplatin resistance cells, on the other hand, had almost no AVD process and VSOR Cl(-) current when treated with cisplatin. Treatment of A549/CDDP cells with trichostatin A (TSA), a drug that inhibits histone deacetylases, partially restored the VSOR Cl(-) current and increased cisplatin-induced cell apoptosis rate. These results suggest that impaired activity of VSOR Cl(-) channels contributes to the cisplatin resistance in A549/CDDP cells.
authors: Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Capital Medical University, Beijing 100069, China.
authors: Xian-Jun
authors: XJ
authors: Min
authors: Hui
authors: H
authors: Li
authors: Sheng-Cai
authors: SC
authors: Hou
authors: Wei
authors: W
authors: He
authors: Jie
authors: J
authors: Liu
authors: Bin
authors: B
authors: Hu
authors: Jun
authors: J
authors: Wang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology*; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D018118:Chloride Channels; D017931:DNA Primers; D006877:Hydroxamic Acids; C012589:trichostatin A; D002945:Cisplatin