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Metabolic flux analysis gives an insight on verapamil induced changes in central metabolism of HL-1 cells

Paper ID Volume ID Publish Year Pages File Format Full-Text
24064 43493 2011 9 PDF Available
Title
Metabolic flux analysis gives an insight on verapamil induced changes in central metabolism of HL-1 cells
Abstract

Verapamil has been shown to inhibit glucose transport in several cell types. However, the consequences of this inhibition on central metabolism are not well known. In this study we focused on verapamil induced changes in metabolic fluxes in a murine atrial cell line (HL-1 cells). These cells were adapted to serum free conditions and incubated with 4 μM verapamil and [U-13C5] glutamine. Specific extracellular metabolite uptake/production rates together with mass isotopomer fractions in alanine and glutamate were implemented into a metabolic network model to calculate metabolic flux distributions in the central metabolism. Verapamil decreased specific glucose consumption rate and glycolytic activity by 60%. Although the HL-1 cells show Warburg effect with high lactate production, verapamil treated cells completely stopped lactate production after 24 h while maintaining growth comparable to the untreated cells. Calculated fluxes in TCA cycle reactions as well as NADH/FADH2 production rates were similar in both treated and untreated cells. This was confirmed by measurement of cell respiration. Reduction of lactate production seems to be the consequence of decreased glucose uptake due to verapamil. In case of tumors, this may have two fold effects; firstly depriving cancer cells of substrate for anaerobic glycolysis on which their growth is dependent; secondly changing pH of the tumor environment, as lactate secretion keeps the pH acidic and facilitates tumor growth. The results shown in this study may partly explain recent observations in which verapamil has been proposed to be a potential anticancer agent. Moreover, in biotechnological production using cell lines, verapamil may be used to reduce glucose uptake and lactate secretion thereby increasing protein production without introduction of genetic modifications and application of more complicated fed-batch processes.

► Central metabolism studied by metabolic flux analysis on HL-1 cells. ► Verapamil halts lactate production by decreasing glucose uptake in HL-1 cells. ► Under normoxia, growth is maintained, by-product secretion significantly reduced. ► Potential application in biotechnology. ► Results also support application of verapamil in cancer therapy.

Keywords
Glucose transport; Central metabolism; Calcium channel blockers; Cardiomyocytes; Warburg effect
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Metabolic flux analysis gives an insight on verapamil induced changes in central metabolism of HL-1 cells
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Publisher
Database: Elsevier - ScienceDirect
Journal: Journal of Biotechnology - Volume 155, Issue 3, 20 September 2011, Pages 299–307
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us