Enhanced anti‐angiogenic activity of novel melatonin‐like agents

Abstract

In the tumor microenvironment, low oxygen tension (hypoxia) is a major driver of angiogenesis, which can lead to metastasis, chemoresistance, and radioresistance. [1][2][3] Under hypoxia, hypoxia-inducible factor-1α (HIF-1α) is stabilized and forms a heterodimer with the constitutively expressed This heterodimer, known as HIF-1, acts as a key regulator of O 2 homeostasis and allows cancer cells to adapt to hypoxic conditions by the transcriptional activation of

Action Sites and Clinical Application of HIF-1α Inhibitors

“…Since the discovery of HIF-1α, researchers have studied and discovered many HIF-1α inhibitors, and a variety of drugs that inhibit the transcriptional activity of HIF-1α have been used in clinical or preliminary trials ( Table 1 ). For example, melatonin and its derivative N-butyryl-5-methoxytryptamine (NB-5-MT) promote the degradation of HIF-1α [ 36 , 37 ]; artepillin C and baccharin can inhibit transcriptional expression of HIF-1α [ 38 ]; MO-460 and EZN-2968 can inhibit the translational activity of mRNA [ 39 , 40 ]; echinomycin blocks HIF-1α binding to HRE [ 41 , 42 ]; and chaetocin and menadione block the formation of the HIF-1α transcription complex [ 43 , 44 ].…”

Regulating the Expression of HIF-1α or lncRNA: Potential Directions for Cancer Therapy

“…Studies have demonstrated that melatonin decreased the level of HIF-1α protein but not mRNA in the cells and additionally decreased the level of HIF-1α target gene expression after the administration of melatonin in kidney HK-2 cells [ 105 ]. In addition, another team has demonstrated that N-butyryl-5-methoxytryptamine (NB-5-MT), a derivative of melatonin, can reduce the expression of HIF-1α protein and the transcription of HIF-1α target genes, and has a high strong anti-angiogenesis effect in tumors, which can be used as a potential new anti-tumor drug [ 106 ].…”

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor

“…Melatonin (also known as N-acetyl-5-methopxytryptamine) is a hormone that is secreted by the pineal gland of the brain in response to the day and night cycles for the regulation of the circadian rhythm. Recent studies have demonstrated that melatonin and its derivatives, such as N-butyryl-5-methoxytryptamine (NB-5-MT), have potent HIF-1α targeting activity through multiple molecular mechanisms [ 61 , 62 ]. Melatonin and NB-5-MT were found to activate PHDs’ activity, facilitating the interaction of HIF-1α protein with pVHL for its proteolysis [ 61 , 62 ].…”

“…Recent studies have demonstrated that melatonin and its derivatives, such as N-butyryl-5-methoxytryptamine (NB-5-MT), have potent HIF-1α targeting activity through multiple molecular mechanisms [ 61 , 62 ]. Melatonin and NB-5-MT were found to activate PHDs’ activity, facilitating the interaction of HIF-1α protein with pVHL for its proteolysis [ 61 , 62 ]. In addition, melatonin increased VHL activity by suppressing the Akt/glycogen synthase kinase-3β (GSK-3β) signaling pathway, and eventually decreased HIF-1α protein stability [ 63 ].…”

“…The HIF-1 inhibitory activity of melatonin and NB-5-MT has been confirmed to significantly inhibit angiogenesis, epithelial-mesenchymal transition (EMT), and tumor growth in various mouse models with xenografted tumors of breast, prostate, and kidney cancer cells [ 62 , 65 , 66 ]. In vivo experiments using a zebrafish xenograft model with a colorectal cancer-derived cell line, HCT116, and, a triple negative breast cancer-derived cell line, MDA-MB-231, also demonstrated that NB-5-MT significantly inhibited tumor angiogenesis and delayed tumor growth [ 61 , 62 ]. Although NB-5-MT has not yet undergone clinical trial, antitumor activity of melatonin has already been confirmed in various cancer types.…”