Paclitaxel affects cytosolic calcium signals by opening the mitochondrial permeability transition pore.
We have characterized the effects of the antimitotic drug paclitaxel (Taxol(TM)) on the Ca(2+) signaling cascade of terminally differentiated mouse pancreatic acinar cells. Using single cell fluorescence techniques and whole-cell patch clamping to record cytosolic Ca(2+) and plasma membrane Ca(2+)-dependent Cl(-) currents, we find that paclitaxel abolishes cytosolic Ca(2+) oscillations and in more than half of the cells it also induces a rapid, transient cytosolic Ca(2+) response. This response is not affected by removal of extracellular Ca(2+) indicating that paclitaxel releases Ca(2+) from an intracellular Ca(2+) store. Using saponin-permeabilized cells, we show that paclitaxel does not affect Ca(2+) release from an inositol trisphosphate-sensitive store. Furthermore, up to 15 min after paclitaxel application, there is no significant effect on either microtubule organization or on endoplasmic reticulum organization. The data suggest a non-endoplasmic reticulum source for the intracellular Ca(2+) response. Using the mitochondrial fluorescent dyes, JC-1 and Rhod-2, we show that paclitaxel evoked a rapid decline in the mitochondrial membrane potential and a loss of mitochondrial Ca(2+). Cyclosporin A, a blocker of the mitochondrial permeability transition pore, blocked both the paclitaxel-induced loss of mitochondrial Ca(2+) and the effect on Ca(2+) spikes. We conclude that paclitaxel exerts rapid effects on the cytosolic Ca(2+) signal via the opening of the mitochondrial permeability transition pore. This work indicates that some of the more rapidly developing side effects of chemotherapy might be due to an action of antimitotic drugs on mitochondrial function and an interference with the Ca(2+) signal cascade.
Kidd
Jackie F
JF
Biomedical Imaging Group, Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Pilkington
Mary F
MF
Schell
Michael J
MJ
Fogarty
Kevin E
KE
Skepper
Jeremy N
JN
Taylor
Colin W
CW
Thorn
Peter
P
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D051379:Mice; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000502:physiology*; D010539:Permeability
D016572:Cyclosporine; D017239:Paclitaxel