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Dysfunction of volume-sensitive chloride channels contributes to cisplatin resistance in human lung adenocarcinoma
Xian-Jun Min1, Hui Li, Sheng-Cai Hou
1Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Capital Medical University, Beijing 100069, China.
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.
Insights
Impaired volume-sensitive outward rectifying (VSOR) chloride channels contribute to cisplatin resistance in lung cancer. Restoring VSOR channel activity may overcome drug resistance.
Area of Science:
- Cell Biology
- Molecular Pharmacology
- Oncology
Background:
- Cisplatin is a standard non-small cell lung cancer treatment.
- Drug resistance limits cisplatin efficacy, with mechanisms not fully understood.
Purpose of the Study:
- Investigate the role of volume-sensitive Cl(-) channels in cisplatin resistance.
- Examine these channels in human lung adenocarcinoma (A549) cells.
Main Methods:
- Patch-clamp recording
- Cell volume measurement
- Apoptosis assays
- A549 and cisplatin-resistant A549/CDDP cells
Main Results:
- Cisplatin induced apoptotic volume decrease (AVD) and VSOR Cl(-) current in wild-type A549 cells.
- Cisplatin-resistant A549/CDDP cells showed impaired AVD and VSOR Cl(-) current.
- Trichostatin A partially restored VSOR Cl(-) current and enhanced apoptosis in A549/CDDP cells.
Conclusions:
- Impaired VSOR Cl(-) channel activity contributes to cisplatin resistance in A549/CDDP cells.
- Targeting VSOR channels could be a strategy to overcome cisplatin resistance in lung cancer.
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