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Title

Fludarabine inhibits Kv1.3 currents in human B lymphocytes

AuthorsVera-Zambrano, Alba; Peraza, Diego A.; Valenzuela, Carmen ; Pérez-Chacón, Gema ; González, Teresa
KeywordsChronic lymphocytic leukemia
B lymphocyte
KV1.3
F-ara-A
Fludarabine
Issue Date2018
Citation5th Symposium on Biomedical Research (2018)
Abstract[Introduction]:Fludarabine (F-ara-A) is a purine analogue commonly used in the treatment of indolent B cell malignancies that interferes with different aspects of DNA and RNA synthesis. KV1.3 potassium channels are membrane proteins involved in the control of K+ homeostasis and in the maintenance of the resting potential of the cell, thus controlling signalling events, proliferation and apoptosis in lymphocytes. The aim of this study was to determine if F-ara-A modulates KV currents in human B lymphocytes. [Material and methods]: We assessed the expression, the activity and the effect of F-ara-A on the KV1.3 channel in BL2 and Dana B cell lines. Currents were registered by whole-cell patch-clamp. Statistical significance was determined by t-Student test or by nonparametric Mann-Whitney test. [Results]: We show that KV1.3 is expressed in both BL2 and Dana B cell lines, although total KV1.3 levels were higher in BL2 compared to those in Dana cells. However, KV currents in the plasma membrane were similar in both cell lines. These KV currents were abrogated by the specific KV1.3 channel inhibitor PAP-1, indicating that most KV currents in these B cell lines are controlled by KV1.3. F-ara-A (3.5 μM), a concentration similar to that achieved in the plasma of fludarabine phosphate-treated patients (3 μM), inhibited KV1.3 currents by 61±6.3% and 52.3±6.3% in BL2 and Dana B cells, respectively. The inhibitory effect of F-ara-A was concentration dependent and showed an IC50 value of 0.36±0.04 μM and a nH value of 1.07±0.15 in BL2 cells and 0.34±0.13 μM (IC50) and 0.77±0.11 (nH) in Dana cells. This inhibitory effect of F-ara-A on the activity of plasma membrane KV1.3 was observed in these cells irrespective of their cytotoxic effect. F-ara-A had no effect on heterologously expressed KV1.3 channels, suggesting an indirect mechanism of inhibition. [Conclusions]: Fludarabine (F-ara-A), a chemotherapeutic drug extensively used in clinics, strongly inhibits KV1.3 currents in B lymphoma and lymphoblastoid cells. Although this inhibitory activity is not sufficient to induce cell death, it might still contribute to the cytotoxic effect of the drug.
DescriptionResumen del trabajo presentado al 5th Symposium on Biomedical Research: "Advances and Perspectives In Pharmacology, Drug Toxicity and Pharmacogenetics", celebrado en Madrid del 15 al 16 de marzo de 2018.
URIhttp://hdl.handle.net/10261/177579
Appears in Collections:(IIBM) Comunicaciones congresos
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