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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Pradimicin-IRD exhibits antineoplastic effects by inducing DNA damage in colon cancer cells

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Autor(es):
de Almeida, Larissa Costa [1] ; Bauermeister, Anelize [2, 1] ; Rezende-Teixeira, Paula [1] ; dos Santos, Evelyne Alves [3] ; Beraldo de Moraes, Luiz Alberto [2] ; Machado-Neto, Joao Agostinho [1] ; Costa-Lotufo, Leticia Veras [1]
Número total de Autores: 7
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] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Sao Paulo - Brazil
[3] Univ Sao Paulo, Inst Biomed Sci, Dept Cell Biol & Dev, Sao Paulo - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Biochemical Pharmacology; v. 168, p. 38-47, OCT 2019.
Citações Web of Science: 1
Resumo

DNA-damaging agents are widely used in cancer therapy; however, their use is limited by dose-related toxicities, as well as the development of drug resistance. Drug discovery is essential to overcome these limitations and offer novel therapeutic options. In a previous study by our research group, pradimicin-IRD-a new polycyclic antibiotic produced by the actinobacteria Amycolatopsis sp.-displayed antimicrobial and potential anticancer activities. In the present study, cytotoxic activity was further confirmed in a panel of five colon cancer, including those with mutation in TP53 and KRAS, the most common ones observed in cancer colon patients. While all tested colon cancer cells were sensitive to pradimicin-IRD treatment with IC50 in micromolar range, non-tumor fibroblasts were significantly less sensitive (p < 0.05). The cellular and molecular mechanism of action of pradimicin-IRD was then investigated in the colorectal cancer cell line HCT 116. Pradimicin-IRD presented antitumor effects occurring after at least 6 h of exposure. Pradimicin-IRD induced statistically significant DNA damage (gamma H2AX and p21), apoptosis (PARP1 and caspase 3 cleavage) and cell cycle arrest (reduced Rb phosphorylation, cyclin A and cyclin B expression) markers. In accordance with these results, pradimicin-IRD increased cell populations in the subG(1) and G(0)/G(1) phases of the cell cycle. Additionally, mass spectrometry analysis indicated that pradimicin-IRD interacted with the DNA double strand. In summary, pradimicin-IRD exhibits multiple antineoplastic activities-including DNA damage, cell cycle arrest, reduction of clonal growth and apoptosis-in the HCT 116 cell line. Furthermore, pradimicin-IRD displays a TP53-independent regulation of p21 expression in HCT 116 TP53(-/-), HT-29, SW480, and Caco-2 cells. This exploratory study identified novel targets for pradimicin-IRD and provided insights for its potential anticancer activity as a DNA-damaging agent. (AU)

Processo FAPESP: 18/17595-0 - Estudo da interação molecular da pradimicina-IRD com o DNA e seu mecanismo de ação em células tumorais
Beneficiário:Larissa Costa de Almeida
Linha de fomento: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 14/50926-0 - INCT 2014: biodiversidade e produtos naturais
Beneficiário:Vanderlan da Silva Bolzani
Linha de fomento: Auxílio à Pesquisa - Programa BIOTA - Temático
Processo FAPESP: 15/17177-6 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer
Beneficiário:Leticia Veras Costa Lotufo
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 17/17648-4 - Abordagem integrada na prospecção sustentável de produtos naturais marinhos: da diversidade a substâncias anticâncer
Beneficiário:Anelize Bauermeister
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 17/24993-0 - Investigação da participação de Stathmin 1 e da instabilidade dos microtúbulos no fenótipo de neoplasias hematológicas
Beneficiário:João Agostinho Machado Neto
Linha de fomento: Auxílio à Pesquisa - Regular