Different Roles For K+ Channels in Cisplatin-resistant Cell Lines Argue Against a Critical Role for These Channels in Cisplatin Resistance

• Published in: Anticancer research 2005-11, Vol.25 (6B), p.4113-4122
• Main Authors: LIANG, Xing-Jie, TAYLOR, Barbara, CARDARELLI, Carol, YIN, Jun-Jie, ANNEREAU, Jean-Philippe, GARFIELD, Susan, WINCOVITCH, Stephen, SZAKACS, Gergely, GOTTESMAN, Michael M, ASZALOS, Adorjan
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Growth Processes - physiology; Cell Line, Tumor; Cell Membrane - physiology; Cisplatin - pharmacology; Drug Resistance, Neoplasm; Ether-A-Go-Go Potassium Channels - biosynthesis; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - metabolism; Ether-A-Go-Go Potassium Channels - physiology; Gene Expression; Humans; Intracellular Membranes - physiology; KB Cells; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Medical sciences; Membrane Potentials - physiology; Mitochondria - physiology; Oligonucleotide Array Sequence Analysis; Omeprazole - pharmacology; Oxygen Consumption; Potassium - metabolism; Potassium Channel Blockers - pharmacology; Tumors
• ISSN: 0250-7005; 1791-7530

Cisplatin resistance has been associated with altered K + fluxes. Here, we focused our investigations on the detection of K + channels in a series of cisplatin-resistant (CP-r) cells with increasing resistance and on the functional relationship of these K + channels to resistance. Microarray analysis and confocal microscopy indicated that there was overexpression of the ether-a-gogo gene (HERG) and the inwardly rectifying potassium channel gene (TWIK) in a human epidermal KB and human liver BEL-7404 carcinoma cell line series selected for cisplatin resistance. With increased resistance, the plasma membrane potential, but not the mitochondrial membrane potential, also increases in these two series. For these reasons, we conducted cell proliferation studies in the presence of either antibodies directed against the detected K + channels, omeprazole (a H + pump inhibitor) or a specific inhibitor of the HERG channel (WAY-123398-A-5). The antibodies and omeprazole influenced cell growth only very slightly. The specific K + channel blocker did not alter cisplatin resistance. We also observed that manipulation of K + fluxes with antibodies and the H + pump with omeprazole resulted in opposite effects on cisplatin resistance in these two cell lines. We conclude that K + and H + homeostasis are not critical factors in cisplatin resistance since they affect cisplatin resistance differently in KB and BEL-7404 cells.