The structural conformation of the tachykinin domain drives the anti-tumoural activity of an octopus peptide in melanoma BRAF
Adenosine Triphosphate
Animals
Antineoplastic Agents
/ pharmacology
Calcium
Cell Line, Tumor
Humans
Melanoma
/ drug therapy
Mice
Mutation
Octopodiformes
/ chemistry
Peptides
/ pharmacology
Proto-Oncogene Proteins B-raf
/ genetics
RNA, Messenger
Reactive Oxygen Species
Tachykinins
/ genetics
Zebrafish
/ genetics
ROS
melanoma
metabolism
mitochondria
tachykinin-receptors
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
22
04
2022
received:
13
10
2021
accepted:
05
05
2022
pubmed:
13
7
2022
medline:
21
9
2022
entrez:
12
7
2022
Statut:
ppublish
Résumé
Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma. We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish). Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAF We unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.
Sections du résumé
BACKGROUND AND PURPOSE
Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma.
EXPERIMENTAL APPROACH
We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish).
KEY RESULTS
Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAF
CONCLUSION AND IMPLICATIONS
We unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.
Substances chimiques
Antineoplastic Agents
0
Peptides
0
RNA, Messenger
0
Reactive Oxygen Species
0
Tachykinins
0
Adenosine Triphosphate
8L70Q75FXE
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Calcium
SY7Q814VUP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4878-4896Informations de copyright
© 2022 British Pharmacological Society.
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