Distinct roles of N-acetyl and 5-methoxy groups in the antiproliferative and neuroprotective effects of melatonin

Ricardo Letra-Vilela, Ana María Sánchez-Sánchez, Ana Maia Rocha, Vanesa Martin, Joana Branco-Santos, Noelia Puente-Moncada, Mariana Santa-Marta, Tiago Fleming Outeiro, Isaac Antolín, Carmen Rodriguez, Federico Herrera

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin's antiproliferative effect in HT22 and sw-1353 cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin's antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine.

Original languageEnglish
Pages (from-to)238-249
Number of pages12
JournalMolecular and Cellular Endocrinology
Publication statusPublished - 15 Oct 2016


  • 5-Methoxy
  • Autophagy
  • Cell proliferation
  • Melatonin
  • N-acetyl
  • Neuroprotection


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