| Texto completo | |
| Autor(es): Mostrar menos - |
Branco, Paola C.
[1]
;
Pontes, Cristine A.
[1]
;
Rezende-Teixeira, Paula
[1]
;
Amengual-Rigo, Pep
[2]
;
Alves-Fernandes, Debora K.
[3]
;
Maria-Engler, Silvya Stuchi
[3]
;
da Silva, Alison B.
[4]
;
Pessoa, Otilia Deusdenia L.
[4]
;
Jimenez, Paula C.
[5]
;
Mollasalehi, Niloufar
[6]
;
Chapman, Eli
[6]
;
Guallar, Victor
[2]
;
Machado-Neto, Joao.
[1]
;
Costa-Lotufo, Leticia V.
[1]
Número total de Autores: 14
|
| Afiliação do(s) autor(es): | [1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Av Prof Lineu Prestes 1524, BR-05508900 Sao Paulo, SP - Brazil
[2] Barcelona Supercomp Ctr, Dept Life Sci, Barcelona 08034 - Spain
[3] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, BR-05508000 Sao Paulo, SP - Brazil
[4] Univ Fed Ceara, Dept Organ & Inorgan Chem, BR-60021 Fortaleza, CE - Brazil
[5] Univ Fed Sao Paulo, Inst Marine Sci, Inst Marine Sci, BR-11070100 Santos, SP - Brazil
[6] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 - USA
Número total de Afiliações: 6
|
| Tipo de documento: | Artigo Científico |
| Fonte: | European Journal of Pharmacology; v. 888, DEC 5 2020. |
| Citações Web of Science: | 0 |
| Resumo | |
Melanoma is a type of skin cancer with an elevated incidence of metastasis and chemoresistance. Such features hamper treatment success of these neoplasms, demanding the search for new therapeutic options. Using a two-step resin-based approach, we recently demonstrated that cytotoxic prodiginines bind to the inhibitor of apoptosis protein, survivin. Herein, we explore the role of survivin in melanoma and whether its modulation is related to the antimelanoma properties of three cytotoxic prodiginines (prodigiosin, cyclononylprodigiosin, and nonylprodigiosin) isolated from marine bacteria. In melanoma patients and cell lines, survivin is overexpressed, and higher levels negatively impact survival. All three prodiginines caused a decrease in cell growth with reduced cytotoxicity after 24 h compared to 72 h treatment, suggesting that low concentrations promote cytostatic effects in SK-Mel-19 (BRAF mutant) and SK-Mel-28 (BRAF mutant), but not in SK-Mel-147 (NRAS mutant). An increase in G1 population was observed after 24 h treatment with prodigiosin and cyclononylprodigiosin in SK-Mel-19. Further studies indicate that prodigiosin induced apoptosis and DNA damage, as detected by increased caspase-3 cleavage and histone H2AX phosphorylation, further arguing for the downregulation of survivin. Computer simulations suggest that prodigiosin and cyclononylprodigiosin bind to the BIR domain of survivin. Moreover, knockdown of survivin increased long-term toxicity of prodigiosin, as observed by reduced clonogenic capacity, but did not alter short-term cytotoxicity. In summary, prodiginine treatment provoked cytostatic rather than cytotoxic effects, cell cycle arrest at G0/G1 phase, induction of apoptosis and DNA damage, downregulation of survivin, and decreased clonogenic capacity in survivin knockdown cells. (AU) | |
| Processo FAPESP: | 15/17177-6 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer |
| Beneficiário: | Leticia Veras Costa Lotufo |
| Modalidade de apoio: | Auxílio à Pesquisa - Programa BIOTA - Temático |
| Processo FAPESP: | 17/09022-8 - Proteínas Inibidoras da Apoptose (IAPs) como alvo terapêutico no melanoma: estudos com prodigininas em células resistentes ao vemurafenibe |
| Beneficiário: | Paola Cristina Branco |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 17/11285-7 - Estudo da contribuição da proteína inibidora de apoptose survivina nos efeitos da prodigiosina e derivados em linhagens de melanoma |
| Beneficiário: | Cristine Araujo de Pontes |
| Modalidade de apoio: | Bolsas no Brasil - Iniciação Científica |