Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells.

Abstract

Blocking calcium entry may prevent normal and pathological cell proliferation. There is evidence suggesting that molecules such as carboxyamidotriazole, widely used in anti-cancer therapy based on its ability to block calcium entry in nonexcitable cells, also have antiproliferative properties. We found that carboxyamidotriazole and the capacitative calcium entry blocker 2-aminoethoxydiphenyl borate inhibited proliferation in HEK-293 cells with IC50 values of 1.6 and 50 microM, respectively. Capacitative calcium entry is activated as a result of intracellular calcium store depletion. However, non-capacitative calcium entry pathways exist that are independent of store depletion and are activated by arachidonic acid and diacylglycerol, generated subsequent to G protein coupled receptor stimulation. We found that carboxyamidotriazole completely inhibited the capacitative calcium entry and had no effect on the amplitude of arachidonic-acid-activated non-capacitative calcium entry. However, investigation of the effects of carboxyamidotriazole on mitochondrial calcium dynamics induced by carbachol, capacitative calcium entry and exogenously set calcium loads in intact and digitonin-permeabilized cells revealed that carboxyamidotriazole inhibited both calcium entry and mitochondrial calcium uptake in a time-dependent manner. Mitochondrial inner-membrane potential was altered by carboxyamidotriazole treatment, suggesting that carboxyamidotriazole antagonizes mitochondrial calcium import and thus local calcium clearance, which is crucial for the maintenance of capacitative calcium entry.

• Authors: Olivier Mignen, Christine Brink, Antoine Enfissi, Aditi Nadkarni, Trevor J Shuttleworth, David R Giovannucci, Thierry Capiod
• Journal: Journal of cell science (J Cell Sci) Vol. 118 Issue Pt 23 Pg. 5615-23 (Dec 01 2005) ISSN: 0021-9533 [Print] England
• PMID: 16306224 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Boron Compounds
• Calcium Channel Blockers
• Triazoles
• carboxyamido-triazole
• 2-aminoethoxydiphenyl borate
• Calcium

Topics

• Boron Compounds (pharmacology)
• Calcium (antagonists & inhibitors, metabolism)
• Calcium Channel Blockers (pharmacology)
• Cell Line
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Intracellular Membranes (drug effects, metabolism)
• Ion Transport (drug effects)
• Kidney (cytology, drug effects, metabolism)
• Mitochondria (drug effects, metabolism)
• Time Factors
• Triazoles (pharmacology)