PUBLICATION
Enhanced anti-angiogenic activity of novel melatonin-like agents
- Authors
- Hwang, S.J., Jung, Y., Song, Y.S., Park, S., Park, Y., Lee, H.J.
- ID
- ZDB-PUB-211230-56
- Date
- 2021
- Source
- Journal of pineal research 71: e12739 (Journal)
- Registered Authors
- Keywords
- HIF-1α, N-butyryl-5-methoxytryptamine, VEGF, angiogenesis, melatonin, melatonin-like molecules
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Cells, Cultured
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors*
- Melatonin/analogs & derivatives*
- Mice
- Mice, Inbred C57BL
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 33955074 Full text @ J. Pineal Res.
Citation
Hwang, S.J., Jung, Y., Song, Y.S., Park, S., Park, Y., Lee, H.J. (2021) Enhanced anti-angiogenic activity of novel melatonin-like agents. Journal of pineal research. 71:e12739.
Abstract
Hypoxia-inducible factor-1 (HIF-1) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N-acetyl-5-methopxytryptamine, is produced naturally by the pineal gland and has anti-angiogenic effects in cancer through its ability to modulate HIF-1α activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half-life. Here, we synthesized melatonin-like molecules with enhanced HIF-1α targeting activity and less toxicity and investigated their effects on tumor growth and angiogenesis, as well as the underlying molecular mechanisms. Among melatonin derivatives, N-butyryl-5-methoxytryptamine (NB-5-MT) showed the most potent HIF-1α targeting activity. This molecule was able to (a) reduce the expression of HIF-1α at the protein level, (b) reduce the transcription of HIF-1α target genes, (c) reduce reactive oxygen species (ROS) generation, (d) decrease angiogenesis in vitro and in vivo, and (e) suppress tumor size and metastasis. In addition, NB-5-MT showed improved anti-angiogenic activity compared with melatonin due to its enhanced cellular uptake. NB-5-MT is thus a promising lead for the future development of anticancer compounds with HIF-1α targeting activity. Given that HIF-1α is overexpressed in the majority of human cancers, the melatonin derivative NB-5-MT could represent a novel potent therapeutic agent for cancer.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping