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Comparison of ion channels in multidrug-resistant and -sensitive human leukemic cells
1Department of Physiology, University of Pennsylvania, Philadelphia 19104-6085.
Abstract:
Tumor cell lines selected to grow in the presence of one "natural product" antineoplastic drug often develop cross-resistance to others. This multidrug resistance (MDR) is believed to be a major problem in cancer therapy. Organic Ca2+-channel blockers, such as verapamil, can reverse this resistance and render MDR cells in culture nearly as sensitive to the antineoplastic drugs as the drug-sensitive cells from which they were derived. It has therefore been suggested that Ca2+ channels may play a role in MDR. To determine directly whether there are electrophysiological correlates of MDR, we used whole-cell and single-channel patch-clamp techniques to survey the ion channels in a drug-sensitive human T-cell leukemia line, CCRF-CEM, and a MDR variant, CEM/VLB100. We found no evidence for a voltage-gated Ca2+ channel. However, we did identify three other current/channel types: a voltage-gated tetrodotoxin-sensitive inward current carried by Na+, a voltage-gated labile outward current carried by K+, and a nonselective cation channel reversing at 0 mV. Drug-sensitive and -resistant cells were the same with respect to the level of expression of these channels.
Insights
Multidrug resistance (MDR) in cancer therapy is a significant challenge. This study found no role for calcium channels in MDR, identifying other ion channels that do not differ between drug-sensitive and resistant cells.
Area of Science:
- Oncology
- Molecular Biology
- Electrophysiology
Background:
- Multidrug resistance (MDR) in cancer cells poses a major challenge in chemotherapy.
- Organic calcium (Ca2+) channel blockers can reverse MDR, suggesting a potential role for Ca2+ channels.
Purpose of the Study:
- To investigate the electrophysiological correlates of MDR in human T-cell leukemia.
- To determine if ion channel expression differs between drug-sensitive and MDR cancer cells.
Main Methods:
- Utilized whole-cell and single-channel patch-clamp techniques.
- Examined ion channel activity in drug-sensitive (CCRF-CEM) and MDR (CEM/VLB100) human T-cell leukemia lines.
Main Results:
- No evidence of voltage-gated Ca2+ channels was found in either cell line.
- Identified voltage-gated sodium (Na+) and potassium (K+) currents, and a nonselective cation channel.
- Expression levels of these identified channels were equivalent in both drug-sensitive and MDR cells.
Conclusions:
- Voltage-gated Ca2+ channels do not appear to play a direct role in the MDR phenotype observed in this T-cell leukemia model.
- The investigated ion channels (Na+, K+, nonselective cation) do not explain the MDR mechanism in this context.