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.

Cell volume regulation in epithelial physiology and cancer

“…In KCP-4 cells it was further shown that restoration of the channel's functional expression leads to a decrease in the cisplatin resistance (Lee et al, 2007). Similar results were obtained in human lung adenocarcinoma cells (Min et al, 2011). In wild type EATC, cisplatin treatment induced an AVD response, whereas MDR-EATC showed almost no AVD response when treated with cisplatin (Poulsen et al, 2010).…”

“…Moreover, some studies have shown a decrease in Cl − permeability in various MDR cell models (Gollapudi et al, 1992; Lee et al, 2007; Poulsen et al, 2010; Min et al, 2011). The MDR-EATC and the KCP-4 human epidermoid cancer cells, which exhibit acquired resistance to cisplatin, both have strongly decreased VRAC activity (Lee et al, 2007; Poulsen et al, 2010).…”

Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

“…78 In several multidrug-resistant cancer cell types, there is a reduction in VRAC, which limits the initial cell shrinkage, and hence protects the cell against apoptosis. 70,74,[80][81][82] Using multidrug-resistant EATC (MDR EATC) as an illustrative example, it is seen from . I/V relationships of the Cl -current in ELA cells in G0, G1, or (S) phase, following exposure to hypotonic extracellular solution and at nominally Ca 2C free concentration.…”

DCPIB, the Proposed Selective Blocker of Volume-Regulated Anion Channels, Inhibits Several Glutamate Transport Pathways in Glial Cells

“…However, several years ago the ethacrinic acid derivative DCPIB was found to selectively block swelling-activated Cl 2 currents (Decher et al, 2001). This compound is now increasingly used for probing the involvement of VRAC in physiologic and pathologic processes (see for example Best et al, 2004;Abdullaev et al, 2006;Harrigan et al, 2008;Rosenberg et al, 2010;Min et al, 2011;Sato et al, 2011).…”