Agomelatine, a Melatonin-Derived Drug, as a New Strategy for the Treatment of Colorectal Cancer

Moreno-SanJuan, Sara; Puentes-Pardo, Jose D.; Casado, J.; Escudero-Feliú, Julia; Khaldy, Hoda; Arnedo, Javier; Carazo, Ángel; León, Josefa

doi:10.3390/antiox12040926

Cited by 6 publications

(1 citation statement)

References 57 publications

(76 reference statements)

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“…This effect might be explained, at least in part, by the influence of melatonin in reducing the hypoxia-inducible factor I alpha (HIF-1α) and Twist1 levels after doxorubicin treatment, leading to chemosensitivity to this anthracycline, the promotion of immunogenic cell death and the inhibition of metastasis [ 130 ]. Melatonin has also been reported to regulate the rhythmicity of Paired-related homeobox protein 1 (PRX1), a transcription factor involved in the activation of the EMT, in colorectal cancer cell lines [ 131 ]. Similarly, melatonin strongly suppresses the migration and invasion of stem cells by a potent suppression of SRY (sex determining region Y)-box (SOX9) in an in vivo model of osteosarcoma [ 132 ].…”

Section: Melatonin As An Inhibitor Of the Epithelial-to-mesenchymal T...mentioning

confidence: 99%

Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer

Martínez-Campa,

Álvarez-García,

Alonso-González

et al. 2024

Cancers

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The epithelial-to-mesenchymal transition (EMT) is a cell-biological program that occurs during the progression of several physiological processes and that can also take place during pathological situations such as carcinogenesis. The EMT program consists of the sequential activation of a number of intracellular signaling pathways aimed at driving epithelial cells toward the acquisition of a series of intermediate phenotypic states arrayed along the epithelial–mesenchymal axis. These phenotypic features include changes in the motility, conformation, polarity and functionality of cancer cells, ultimately leading cells to stemness, increased invasiveness, chemo- and radioresistance and the formation of cancer metastasis. Amongst the different existing types of the EMT, type 3 is directly involved in carcinogenesis. A type 3 EMT occurs in neoplastic cells that have previously acquired genetic and epigenetic alterations, specifically affecting genes involved in promoting clonal outgrowth and invasion. Markers such as E-cadherin; N-cadherin; vimentin; and transcription factors (TFs) like Twist, Snail and ZEB are considered key molecules in the transition. The EMT process is also regulated by microRNA expression. Many miRNAs have been reported to repress EMT-TFs. Thus, Snail 1 is repressed by miR-29, miR-30a and miR-34a; miR-200b downregulates Slug; and ZEB1 and ZEB2 are repressed by miR-200 and miR-205, respectively. Occasionally, some microRNA target genes act downstream of the EMT master TFs; thus, Twist1 upregulates the levels of miR-10b. Melatonin is an endogenously produced hormone released mainly by the pineal gland. It is widely accepted that melatonin exerts oncostatic actions in a large variety of tumors, inhibiting the initiation, progression and invasion phases of tumorigenesis. The molecular mechanisms underlying these inhibitory actions are complex and involve a great number of processes. In this review, we will focus our attention on the ability of melatonin to regulate some key EMT-related markers, transcription factors and micro-RNAs, summarizing the multiple ways by which this hormone can regulate the EMT. Since melatonin has no known toxic side effects and is also known to help overcome drug resistance, it is a good candidate to be considered as an adjuvant drug to conventional cancer therapies.

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Section: Melatonin As An Inhibitor Of the Epithelial-to-mesenchymal T...mentioning

confidence: 99%

Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer

Martínez-Campa,

Álvarez-García,

Alonso-González

et al. 2024

Cancers

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Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies

Preciado-A,

Yepes,

Herrera-R

et al. 2024

Med Chem Res

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Considering the important increase in the incidence and mortality of colorectal cancer, it is necessary to develop new strategies in the search for new alternatives against this disease. Hence, we designed and synthesized a new series of monastrol/melatonin hybrids and evaluated them in vitro and in silico to determine the potential of these new chemical entities on this type of cancer. To achieve this goal, the different compounds were evaluated in human colorectal adenocarcinoma cells SW480, while establishing the selective potential of the hybrids through the nonmalignant human colon mucosal epithelial cell line (NCM460). According to the results, hybrids 6a, 6c, 6i, and 6j displayed the best response, with IC50 values in the range of 5.2 and 6.3 μM, inducing important changes depending on concentration and time. In addition, these compounds were extremely active in comparison to the single molecules, and they were slightly more selective than the reference drug (5 fluorouracil, 5-FU). Besides, an optimal pharmacokinetic and toxicological profile was also estimated for hybrids 6a, 6c, 6i, and 6j. Altogether, novel hybrids of monastrol-MLT, in particular, 6a (-H), 6c (3-OMe), 6i (3,4-OMe), and 6j (3,5-OMe) could be addressed as starting points for further pharmacological studies concerning to combat colorectal cancer.

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Melatonin in cancer biology: pathways, derivatives, and the promise of targeted delivery

Yi,

Tang,

et al. 2024

Drug Metabolism Reviews

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Agomelatine, a Melatonin-Derived Drug, as a New Strategy for the Treatment of Colorectal Cancer

Cited by 6 publications

References 57 publications

Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer

Melatonin and Its Role in the Epithelial-to-Mesenchymal Transition (EMT) in Cancer

Novel monastrol/melatonin hybrids as a new approach for colorectal cancer intervention: design, synthesis, biological activity, and drug-likeness modeling studies

Melatonin in cancer biology: pathways, derivatives, and the promise of targeted delivery

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