Cellular uptake of (99m)TcN-NOET in human leukaemic HL-60 cells is related to calcium channel activation and cell proliferation.
OBJECTIVE
A major goal of nuclear oncology is the development of new radiolabelled tracers as proliferation markers. Intracellular calcium waves play a fundamental role in the course of the cell cycle. These waves occur in non-excitable tumour cells via store-operated calcium channels (SOCCs). Bis(N-ethoxy, N-ethyldithiocarbamato) nitrido technetium (V)-99m ((99m)TcN-NOET) has been shown to interact with L-type voltage-operated calcium channels (VOCCs) in cultured cardiomyocytes. Considering the analogy between VOCCs and SOCCs, we sought to determine whether (99m)TcN-NOET also binds to activated SOCCs in tumour cells in order to clarify the potential value of this tracer as a proliferation marker.


METHODS
Uptake kinetics of (99m)TcN-NOET were measured in human leukaemic HL-60 cells over 60 min and the effect of several calcium channel modulators on 1-min tracer uptake was studied. The uptake kinetics of (99m)TcN-NOET were compared both with the variations of cytosolic free calcium concentration measured by indo-1/AM and with the variations in the SG2M cellular proliferation index.


RESULTS
All calcium channel inhibitors significantly decreased the cellular uptake of (99m)TcN-NOET whereas the activator thapsigargin induced a significant 10% increase. In parallel, SOCC activation by thapsigargin, as measured using the indo-1/AM probe, was inhibited by nicardipine. These results indicate that the uptake of (99m)TcN-NOET is related to the activation of SOCCs. Finally, a correlation was observed between the tracer uptake and variations in the proliferation index SG2M.


CONCLUSIONS
The uptake of (99m)TcN-NOET seems to be related to SOCC activation and to cell proliferation in HL-60 cells. These results indicate that (99m)TcN-NOET might be a marker of cell proliferation.
Guillermet
Stephanie
S
INSERM 0340 Radiopharmaceutiques Biocliniques, Université de Grenoble, 38700 La Tronche, France.
Vuillez
Jean-Philippe
JP
Fontaine
Eric
E
Caravel
Jean-Pierre
JP
Marti-Batlle
Danièle
D
Pasqualini
Roberto
R
Fagret
Daniel
D
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D049109:Cell Proliferation; D018922:HL-60 Cells; D006801:Humans; D015640:Ion Channel Gating; D008657:Metabolic Clearance Rate; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013859:Thiocarbamates / Q000493:pharmacokinetics*
D015220:Calcium Channels; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D013859:Thiocarbamates; D002118:Calcium; C093922:technetium Tc 99m, bis(N-ethoxy-N-ethyldithiocarbamato)nitrido-