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Verapamil-induced blockade of voltage-activated K+ current in small-cell lung cancer cells
J J Pancrazio1, M P Viglione, R J Kleiman
1Department of Biomedical Engineering, University of Virginia Health Sciences Center, Charlottesville 22908.
Abstract:
Verapamil, Ca++ channel antagonist, has proven clinically useful in the reversal of multiple drug resistance, which is a major detriment to chemotherapy. Recently, verapamil alone has been shown to diminish proliferation in a variety of neoplastic cell lines. Using the patch-clamp technique, the action of verapamil on voltage-gated K+ channels in two cell lines of human small-cell carcinoma of the lung, NCI-H146 and NCI-H82, was investigated. With inward Na+ current suppressed, virtually all control cells exhibited a slowly inactivating outward current that was insensitive to alterations in the external Ca++ concentration. Externally applied verapamil enhanced the rate and extent of outward K+ current (IK) inactivation. Verapamil at a concentration of 20 microM diminished peak IK, evoked by a test pulse to +60 mV from a holding potential of -80 mV, from 1.38 +/- 0.11 nA (mean +/- S.E.M., n = 29 cells) to 0.56 +/- 0.13 nA (n = 11) and caused IK to decay to less than 20% of the peak current within 60 msec. After blocking IK and Na+ current, Ca++ current (ICa) was measured in the presence of 10 mM Ca++. The addition of 100 microM verapamil to the external bath resulted in a 53% reduction of H146 ICa. Peak ICa fell from 81 +/- 9 pA (n = 22) to 38 +/- 8 pA (n = 12). Examination of the whole-cell K+ current on single cells before and immediately after the addition of 100 microM verapamil clearly revealed that the drug had no effect on the initial activation phase of IK, suggesting that K+ channels first open before interacting with the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Verapamil, a calcium channel blocker, affects ion channels in lung cancer cells. It inhibits potassium current inactivation and reduces calcium current, impacting cell proliferation.
Area of Science:
- * Pharmacology
- * Cellular Electrophysiology
- * Oncology
Background:
- * Verapamil is a calcium (Ca++) channel antagonist with clinical utility in reversing multidrug resistance.
- * Verapamil has demonstrated anti-proliferative effects on various neoplastic cell lines.
- * Small-cell lung carcinoma (SCLC) presents significant therapeutic challenges.
Purpose of the Study:
- * To investigate the effects of verapamil on voltage-gated potassium (K+) and calcium (Ca++) channels in human small-cell lung cancer cell lines.
- * To elucidate the electrophysiological mechanisms underlying verapamil's action on NCI-H146 and NCI-H82 cells.
Main Methods:
- * Patch-clamp technique was employed to record ionic currents.
- * Voltage-gated sodium (Na+) currents were suppressed to isolate K+ and Ca++ currents.
- * Verapamil's effects on outward K+ current (IK) and inward Ca++ current (ICa) were assessed.
Main Results:
- * Verapamil enhanced the inactivation rate and extent of outward K+ current (IK) in both cell lines.
- * A 20 microM concentration of verapamil significantly reduced peak IK.
- * 100 microM verapamil decreased peak Ca++ current (ICa) by 53% in NCI-H146 cells.
- * Verapamil did not affect the initial activation phase of IK, suggesting post-opening interaction.
Conclusions:
- * Verapamil modulates ion channel function in small-cell lung cancer cells.
- * The drug's effects on K+ and Ca++ currents may contribute to its observed anti-proliferative activity.
- * Further research is warranted to explore verapamil's therapeutic potential in lung cancer.