Les cellules traitées avec le peptide expérimental Rb4 ne se sont pas répliquées et ont formé des amas, perdant leur morphologie naturelle après seulement 24 heures d’incubation.
Le traitement expérimental avec une molécule dérivée d’une protéine a réduit la croissance tumorale et les métastases, et a augmenté le taux de survie de 25%.
Une étude récente publiée dans Scientific Reports démontre l’efficacité du Rb4, un peptide développé par des scientifiques brésiliens, pour combattre la croissance du cancer dans un modèle animal, en particulier le mélanome malin. Le peptide a également le potentiel de traiter les tumeurs résistantes aux médicaments.
Rb4 provoque la nécrose des cellules de mélanome murin et diminue la viabilité des cellules cancéreuses humaines dans des essais précliniques in vitro et in vivo. Les cellules tumorales de l’expérience ont perdu plasma membrane integrity, and mitochondria (energy-producing organelles) dilated even in the absence of chromatin condensation, a morphological hallmark of apoptosis. The researchers admit that they still don’t fully understand what causes this necrosis.
The peptide also reduced lung metastasis and decreased subcutaneous melanoma development in mice. The findings suggest that Rb4 acts directly on tumors, inducing the expression of two damage-associated molecular patterns (DAMPs) that cause immunogenic melanoma cell death.
Before and after the action of peptide Rb4 on tumor cells. Credit: Fabrício Castro Machado
“We do basic science in a search for novel molecules. In this study Rb4, which is derived from proteolipid protein 2 [PLP2]L’article traite de certains aspects de cette molécule, notamment de son rôle dans le développement de la nécrose, un type spécifique de mort cellulaire, en particulier dans le mélanome, mais la manière dont cette nécrose se produit et se développe n’est pas claire. L’article discute de certains aspects de la composition morphologique du peptide et des effets finaux de son contact”, a déclaré à l’Agência FAPESP Fabrício Castro Machado, co-auteur de l’article.
M. Machado est un ancien membre de l’unité de cancérologie expérimentale du département de microbiologie, d’immunologie et de parasitologie de l’université fédérale de São Paulo (UNIFESP) au Brésil, et est actuellement chercheur chez Recepta Biopharma (ReceptaBio), une société de biotechnologie brésilienne qui développe des médicaments contre le cancer (d’où le “Rb” dans le nom du peptide).
Avec le soutien de la FAPESP, un groupe dirigé par Luiz Rodolpho Travassos, professeur émérite de l’UNIFESP, a commencé à mener les recherches. Les auteurs de l’article rendent hommage à Travassos, décédé en 2020. Il a publié plus de 230 articles dans des revues scientifiques de premier plan, dont beaucoup sur l’étude des peptides et des peptidases (enzymes qui décomposent les protéines en peptides et finalement en
;” data-gt-translate-attributes=”[{” attribute=””>amino acids) in infectious diseases and cancer. Owing to this interest, in 2008 he contacted ReceptaBio, whose CEO is José Fernando Perez, a former Scientific Director of FAPESP (1993-2005).
“Professor Travassos identified several sequences of bioactive peptides, small molecules based on antibodies developed by ReceptaBio. Rb4 was also identified during this process of searching for novel molecules, although it isn’t derived from antibodies. We have another, Rb9, which is at a more advanced research stage, with several publications and patents, but still at the preclinical stage,” said Alice Santana Morais, a research and development analyst at ReceptaBio and corresponding author of the article.
In 2016, the scientists described the structure of Rb9 and its action mechanism as an inhibitor of melanoma cells. A more recent article published in 2020 showed that Rb9 acts as an immunomodulator and can be used to control tumor progression.
“Whether in academia or in companies like ReceptaBio, we need to combine efforts to conduct research. We’re looking for partners to boost the drug development process, which is lengthy and painstaking and requires discussion, details, and an exchange of experiences,” Morais said.
Promising results
Novel cancer treatments developed in recent years include peptide-based chemotherapy. Peptides have received increasing attention not only because they can bind to the membranes of tumor cells, but also because they have low molecular weights, good cell tissue penetration, and low toxicity for normal tissue. They can be used as cell reagents, ligands, vaccines, and carriers of cytotoxic drugs in peptide-alone therapy or peptide-conjugated materials.
In the study on Rb4’s anti-tumor action, the group found that the peptide interfered with the morphology, replication, and association of B16F10-Nex2 melanoma cells cultured in the laboratory. In contrast with controls, cells treated with Rb4 did not replicate and formed clusters, losing their natural morphology after incubation for at most 24 hours.
In addition, Rb4 reduced the number of lung metastatic nodules in a syngeneic melanoma model (involving tumor tissues from mice with the same genetic makeup). This result was detected after melanoma cells were injected intravenously into the mice. They were given five intraperitoneal injections of the peptide (300 micrograms per animal) on alternate days, delaying tumor growth by up to 40 days.
The survival rate of mice treated with Rb4 was significantly greater than that of the controls, increasing group survival by more than 25% and up to 10 days.
Melanoma originates in cells that produce melanin, the pigment that gives color to the skin. It can appear in various parts of the body. Although skin cancer is the most common form of cancer in Brazil, accounting for about 30% of all cases, melanoma represents only 3% of malignant neoplasias. It is the most life-threatening, however, because of the high probability of spreading to other organs (metastasis).
Around 8,400 cases of melanoma occur each year in Brazil, according to estimates by the National Cancer Institute (INCA). The disease caused 1,978 deaths in 2019.
Reference: “PLP2-derived peptide Rb4 triggers PARP-1-mediated necrotic death in murine melanoma cells” by Vera S. C. Maia, Rodrigo Berzaghi, Denise C. Arruda, Fabrício C. Machado, Leticia L. Loureiro, Pollyana M. S. Melo, Alice S. Morais, Alexandre Budu and Luiz R. Travassos, 21 February 2022, Scientific Reports.
DOI: 10.1038/s41598-022-06429-8
