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Prevention of Photocarcinogenesis by Agonists of 5-HT1A and Antagonists of 5-HT2A Receptors

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Abstract

Exposure to UV radiation is the principal cause of nonmelanoma skin cancer, a process in which serotonin (5-HT) is intimately involved. This review focuses on the potential of serotonin receptors, namely 5-HT1/2A, as therapeutic targets for prevention of photocarcinogenesis. UV-induced immunosuppression is triggered by a cascade of events initiated when cis-urocanic acid, a UV photoreceptor present in the skin, binds to the serotonin receptor. Serotonin receptor antagonists will therefore attempt to block this association, and in turn, prevent skin cancer induction. In addition, 5-HT2A receptor antagonists are also capable of regulating DNA repair, including the acceleration of nucleotide excision repair. At the same time, UV-induced formation of reactive oxygen species is also reduced by these agents. Since the involvement of serotonin in photocarcinogenesis process is somewhat underexplored as a pertinent therapeutic effect, this review intends to reveal the use of serotonergic drugs as an important strategy to prevent and/or inhibit photocarcinogenesis. Considering the emergency of developing novel therapeutic strategies for skin cancer management, the use of these agents, whose benefits have partially been studied, may be crucial especially if topically applied. Topical nanoformulations containing serotonin receptor agonists and/or antagonists also represent a pioneer concept in this area.

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Article Open access 13 July 2020

Sweta Subhadarshani, Mohammad Athar & Craig A. Elmets

Abbreviations

FapydG:

2,6-Diamino-4-hydroxy-5-formamidopyrimidine

SERT or 5-HTT:

5-Hydroxytryptamine transporter

5-HIAL:

5-Hydroxy-3-indolacetaldehyde

5-HIAA:

5-Hydroxy-3-indolacetic acid

5-HT:

5-Hydroxytryptamine or serotonin

5-HTR:

5-Hydroxytryptamine receptors

5-HTPOL:

5-Hydroxytryptophol

5-MT:

5-Methoxytryptamine

5-HTP:

5-OH-tryptophan

8-OH-dG:

8-Hydroxy-2-deoxyguanosine

8-oxo-dG:

8-Oxo-7,8-dihydroguanine

OGG1:

8-Oxoguanine DNA glycosylase-1

ADH:

Alcohol dehydrogenase

ALDH2:

Aldehyde dehydrogenase

ALDR:

Aldehyde reductase

Ag:

Antigens

AIF:

Apoptosis inducing factor

BCCs:

Basal cell carcinomas

BER:

Base excision repair

BH4:

Cofactor 6-tetrahydrobiopterin

CHS:

Contact hypersensitivity

CPD:

Cyclobutane-type pyrimidine dimers

COX:

Cyclooxygenase

DAG:

Diacylglycerol

DAT:

Dopamine transporter

APC:

Epidermal antigen-presenting cells

FAD:

Flavin adenine dinucleotide

Th:

Helper T cells

HSV:

Herpes simplex virus

HPA:

Hypothalamic-pituitary-adrenal axis

IP3:

Inositol 1,4,5-triphosphate

IFN-γ:

Interferon gamma

IL:

Interleukins

l-aromatic AAD:

l-amino acid decarboxylase

LC:

Langerhans cells

MHC:

Major histocompatibility complex

MAO:

Monoamine oxidase

NAS:

N-acetylserotonin

NK:

Natural killer cells

NO:

Nitric oxide

NMSC:

Nonmelanoma skin cancers

NER:

Nucleotide excision repair

OS:

Oxidative stress

PI:

Phosphoinositol

PLC:

Phospholipase C

PDT:

Photodynamic therapy

PAF:

Platelet-activating factor

PCR:

Polymerase chain reaction

OCT:

Polyspecific organic cation transporters

PG:

Prostaglandin

PKA:

Protein kinase A

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

Treg:

Regulatory T cells

SSRIs:

Selective serotonin reuptake inhibitors or serotonin-specific reuptake inhibitor

SCCs:

Squamous cell carcinomas

TGF-β:

Transforming growth factor

TPH:

Tryptophan hydroxylase

TNF-α:

Tumor necrosis factor-α

UVR:

Ultraviolet radiation

UCA:

Urocanic acid

VMAT:

Vesicular monoamine transporter

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Authors Contributions

ACM did the main bibliographic search and wrote the main sections of the manuscript. AA/SS and SR/HR/HO revised the photocarcinogenesis and serotonin sections, respectively. All authors participated in review’s design, coordination, and final revision.

Conflict of Interests

All authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Faculdade de Farmácia da Universidade de Lisboa, Lisbon, Portugal

    Ana Catarina Menezes

  2. Nanomedicine and Drug Delivery Systems group of iMed.UL, Lisbon, Portugal

    Sara Raposo, Sandra Simões, Helena Ribeiro & Andreia Ascenso

  3. Department Biology, Laboratory of Biotechnology and Cytomics, CESAM, Universidade de Aveiro, Aveiro, Portugal

    Helena Oliveira

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  1. Ana Catarina Menezes
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  2. Sara Raposo
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  3. Sandra Simões
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  4. Helena Ribeiro
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  6. Andreia Ascenso
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Corresponding author

Correspondence to Andreia Ascenso.

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Table 1

5-HT1R Agonists: chemical, biological and therapeutic properties of new and commercial drugs [112–119]. NF = Not Found; NA = Not Applicable. (DOCX 99 kb)

Table 2

5-HT2R Antagonists: chemical, biological and therapeutic properties of new drugs (Table 2A) and commercialized drugs (Table 2B) [112–119]. NF = Not Found; NA = Not Applicable Note: some solubility data may vary depending on the literature source. (DOCX 500 kb)

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Menezes, A.C., Raposo, S., Simões, S. et al. Prevention of Photocarcinogenesis by Agonists of 5-HT1A and Antagonists of 5-HT2A Receptors. Mol Neurobiol 53, 1145–1164 (2016). https://doi.org/10.1007/s12035-014-9068-z

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