| Full text | |
| Author(s): Show less - |
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]
Total Authors: 14
|
| Affiliation: | [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
Total Affiliations: 6
|
| Document type: | Journal article |
| Source: | European Journal of Pharmacology; v. 888, DEC 5 2020. |
| Web of Science Citations: | 0 |
| Abstract | |
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) | |
| FAPESP's process: | 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds |
| Grantee: | Leticia Veras Costa Lotufo |
| Support Opportunities: | BIOTA-FAPESP Program - Thematic Grants |
| FAPESP's process: | 17/09022-8 - Inhibitory Apoptosis Proteins (IAPs) as therapeutic targets in melanoma: studies with prodiginines in vemurafenibe-resistant cells |
| Grantee: | Paola Cristina Branco |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 17/11285-7 - Study of the contribution of the inhibitory apoptosis protein survivin on effects of prodigiosin and derivatives in melanoma lineages |
| Grantee: | Cristine Araujo de Pontes |
| Support Opportunities: | Scholarships in Brazil - Scientific Initiation |