Notch receptors as a therapeutic target in melanoma: a narrative bibliographic review

Melanoma is the skin cancer with higher mortality and more and more cases are arising every year. Overexpression of Notch signaling pathway elements have already been found in primary and metastatic melanoma lineages, and directly correlated to melanoma’s development, growth, angiogenesis, metastasis, and resistance to treatment. Thus, target therapy against Notch in melanoma presents a high potential for the treatment of this type of cancer. In this review we aim to perform a narrative review on melanoma’s possible treatments targeting the Notch pathway. We searched literature about Notch signaling pathway inhibitors in human cutaneous melanoma published between 2000 and 2020 using MEDLINE (PubMed), LILACS (Virtual Health Library) and Cochrane Library databases. The selected articles were analyzed, summarized, tabulated, and used to produce the present narrative review. The 24 selected articles, as well as articles referenced in them, presented as targeting therapy against Notch, γ-secretase inhibitors (GSIs), primarily, but also gliotoxin, honokiol, phospholipase A2, andrographolide and monoclonal antibodies, that, however, were not directly studied in melanoma. Another therapy that indirectly interfered in the Notch signaling pathway and was found in these articles were G9a inhibitors. Analyzing the collected data, it was possible to conclude that GSIs, more extensively studied, are probably not the best option for melanoma’s treatment, exceeding specific scenarios or through their concomitant use with other pathways inhibitors. The use of the other compounds, on the other hand, has greater potential, however, more studies are needed to prove its effectiveness and viability for the treatment of human cutaneous melanoma.


Introduction
Nowadays, even with the therapeutic advance of immunotherapy and target therapy, melanoma is still the skin cancer with the greatest mortality.1 According to the International Agency for Research on Cancer, it is expected an increase of up to 62% in the incidence of melanoma cases and an increase of 74% of deaths from this type of cancer by 2040. The main Notch target genes are genes from the Hes and Hey family, among other targets 4 .
Each set of terms used were tabulated to determine the number of "results"; "selected articles after reading the abstract" and "selected articles after reading the full text". Search strategy in each database is described in table 1.

Database Search strategy
Medline (

Gamma-secretase inhibitors (GSI)
Since the γ-secretase complex is essential for the second cleavage of Notch receptors, originating its active form, NICD, it has been studied as a target for therapy in melanomas, using GSIs. cells. In addition, β-catenin was also affected, with its levels reduced in primary cells 22   and suppressing lung metastasis. These effects were associated with Andro's ability to nullify the Notch1-mediated CD133-dependent p38 MAPK activation pathway 49 .

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these compounds may be a good option for use in precision medicine, an area that considers the genetic differences between individuals when prescribing specific treatments, which may have more or less therapeutic efficiency or toxic effects in different populational groups, or, still, in association with inhibitors of other pathways that can potentialize its effect in the inhibition of melanoma cells.
Furthermore, when compared to other compounds such as Gliotoxin and HNK, GSIs have been shown to be less effective in inhibiting melanoma cells 44,48 . These compounds, dssPLA2 45 and Andro 49 were shown to be potential candidates for the treatment of melanoma by inhibiting the Notch signaling pathway, inhibiting melanoma cells and even reducing tumor volume, also presenting low toxicity. Although studies of monoclonal antibodies have not been found as a target therapy for Notch in melanoma, its studies in other types of cancers demonstrated that they have lower toxicity if compared with GSI . 35,36 .
Methyltransferase inhibitors, such as G9a inhibitors, interfere with the expression of the Notch signaling pathway and have shown promising results with high therapeutic potential, especially in cases where the Notch1 pathway is involved, within a broader concept of precision medicine. This concept encourages the study of other substances, such as UNC0642 or its derivatives, with greater liposolubility, greater power for cellular availability and less toxicity 21,38 .

Conclusion
It is certain that the Notch signaling pathway can contribute to the appearance and progression of melanoma, therefore, the inhibition has relevant potential for the treatment of this type of cancer. Considering what was exposed in this review, GSIs are not the best option, except for specific scenarios, which can be determined by