Spontaneous Ca2+ oscillations are restricted to the
G1/S phase transition in P19 CSCs, suggesting a role
for Ca2+ in stem cell cycle progression [41]. In fact, we
have recently reported that P19 stem cells present low
cytosolic calcium levels, which are increased during cell
differentiation [23]. The higher concentrations of free
calcium found in P19 cells grown in galactose medium
are correlated with the changes found on cell cycle
progression. Accordingly, the effect of melatonin on free
Ca2+ was also dissimilar. Glu-CSCs showed increased Ca2+
levels upon melatonin treatment while having no effect
on cell viability. Conversely, melatonin-treated cells
grown in galactose (glucose-free), glutamine/pyruvatecontaining
medium showed cell cycle arrest at S-phase,
decreased cell viability and low intracellular free Ca2+
concentrations which, according with our previous results
[23], seem to be required at high levels during the process
of cell differentiation and mitochondrial maturation. These
different results, which depend on the cellular metabolic
state, are probably influenced by the lower calcium
retention ability of mitochondria from differentiated
cells than those from Glu-CSCs [23]. Thus, the effects of
melatonin on calcium signaling [25, 42] may play a role
in mediating its growth-inhibitory action in cells with an
active mitochondrial metabolism.