Melatonin is an indoleamine synthesized in the pineal gland, and after its release into the blood, it has an extensive repertoire of biological activities, including antitumoral properties. In this study, we found that melatonin reduced the growth of the human melanoma cells SK-MEL-1. The antiproliferative effect was associated with an alteration in the progression of the phases of the cell cycle and also with an increase in tyrosinase activity, the key regulatory enzyme of melanogenesis. Antagonists for melatonin membrane receptors (luzindole and 4-P-PDOT) and the general G-coupled receptor inhibitor, pertussis toxin, did not prevent the melatonin-induced cell growth arrest; this suggests a mechanism independent of G-coupled membrane receptors. In contrast, p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway seems to play a significant role in cell growth inhibition by melatonin. The indoleamine-induced phosphorylation of p38 MAPK and the effect on cell proliferation were abrogated by the specific inhibitor SB203580. Furthermore, comparative studies with known antioxidants such as N-acetyl-l-cysteine and trolox indicate that the growth of SK-MEL-1 cells is highly sensitive to antioxidants.
Melatonin is an indoleamine that is synthesized in the pineal gland and has an extensive repertoire of biological activities. In the present study, we found that melatonin reduced the growth of the human myeloid leukemia cells HL-60, inhibiting progression from G(1) to S phase of the cell cycle and increasing apoptotic cell death. Furthermore, melatonin treatment elevated cytochrome c release from mitochondria and augmented caspase-3 and caspase-9 activities. Upregulation of Bax and downregulation of Bcl-2 was also observed upon melatonin treatment. The effects of melatonin were found not to be mediated by membrane receptors for the indoleamine. Together, our results suggest that melatonin reduces the viability of HL-60 cells via induction of apoptosis primarily through regulation of Bax/Bcl-2 expression.
In the present study, the cytotoxicity
of 30 diterpenoids with an abietane or a halimane skeleton was determined
against five human tumor cell lines (HL-60, U937, Molt-3, SK-MEL-1,
and MCF-7). Diterpenoids containing an abietane skeleton including
taxodone (1) and taxodione (2), as well
as the semisynthetic derivatives 12, 14, 15, 17, and 22, were the most cytotoxic
compounds for human leukemia cells. Overexpression of the protective
mitochondrial proteins Bcl-2 and Bcl-xL did not confer
resistance to abietane diterpene-induced cytotoxicity. Studies performed
on HL-60 cells indicated that growth inhibition triggered by compounds 1, 12, 14, and 15 was
caused by induction of apoptosis. This was prevented by the nonspecific
caspase inhibitor Z-VAD-FMK and, in the case of compounds 14 and 15, reduced by the selective caspase-8 inhibitor
Z-IETD-FMK. Cell death induced by these abietane diterpenes was found
to be associated with the release of mitochondrial proteins, including
cytochrome c, Smac/DIABLO, and AIF (apoptosis-inducing
factor), accompanied by dissipation of the mitochondrial membrane
potential (ΔΨ), and modulated by inhibition of extracellular
signal-regulated kinases signaling and the p38 mitogen-activated protein
kinase pathway.
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