Pancreatic stellate cells (PSC) play a major role in the formation of fibrotic tissue in pancreatic
tumors. On its side,
melatonin is a putative therapeutic agent for
pancreatic cancer and
inflammation. In this work, the actions of
melatonin on PSC subjected to
hypoxia were evaluated.
Reactive oxygen species (ROS) generation reduced (GSH) and oxidized (
GSSG) levels of
glutathione, and
protein and
lipid oxidation were analyzed. The phosphorylation of nuclear factor erythroid 2-related factor (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (
NF-kB), and the regulatory
protein nuclear factor of kappa light
polypeptide gene enhancer in B-cells inhibitor-alpha (IκBα) was studied. The expression of Nrf2-regulated
antioxidant enzymes,
superoxide dismutase (SOD)
enzymes,
cyclooxygenase 2 (COX-2),
interleukin-6 (IL-6) and
tumor necrosis factor-α (TNF-α) were also studied. Total
antioxidant capacity (TAC) was assayed. Finally, cell viability was studied. Under
hypoxia and in the presence of
melatonin generation of ROS was observed. No increases in the oxidation of
proteins or
lipids were detected. The phosphorylation of Nrf2 and the expression of the
antioxidant enzymes catalytic subunit of
glutamate-cysteine ligase,
catalase,
NAD(P)H-
quinone oxidoreductase 1,
heme oxygenase-1, SOD1, and of SOD2 were augmented. The TAC was increased.
Protein kinase C was involved in the effects of
melatonin.
Melatonin decreased the GSH/
GSSG ratio at the highest concentration tested. Cell viability dropped in the presence of
melatonin. Finally,
melatonin diminished the phosphorylation of
NF-kB and the expression of COX-2,
IL-6, and TNF-α. Our results indicate that
melatonin, at pharmacological concentrations, modulates the red-ox state, viability, and the expression of proinflammatory mediators in PSC subjected to
hypoxia.