Study of pradimicina-IRD molecular interaction with DNA and its tumor cell mechanism of action

• Grant number: 18/17595-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2019
• End date: June 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Leticia Veras Costa Lotufo
• Grantee: Larissa Costa de Almeida
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds, AP.BTA.TEM
• Associated scholarship(s): 20/01125-5 - Study of the TRAIL-sensitizing mechanism of action of marine natural products, BE.EP.DD

Abstract

Most of the antineoplastic drugs used in clinical practice are derived from natural products. Great efforts have been applied to identify new compounds to generate new therapeutic opportunities for the treatment of Cancer. In a previous study by our research group, pradimicin-IRD, a new polycyclic antibiotic derivative of the actinobacterium Amycolatopsis sp., showed antimicrobial and cytotoxic activities. Our results so far point to the time-dependent cytotoxicity of pradimicin-IRD in HCT 116 cells, with reduction of cell density and viable cells, and IC50 in micromolar order. Additionally, it has been demonstrated that after 6 hours of treatment, pradimicin-IRD has cytotoxic activity and reduces clonogenic capacity. The apoptotic effect of pradimicin-IRD was confirmed by the induction of apoptotic proteins, such as caspase-3 and PARP-1 cleavage, which may be related to DNA damage - observed by phosphorylation of H2AX protein and induction of p21 expression. Cellular and molecular analyzes indicate that pradimicin-IRD potentially induces DNA damage, cell cycle arrest, and apoptosis in the HCT 116 colorectal carcinoma cell line. Further studies aimed at identifying mechanisms of pradimicin-IRD DNA damage will be conducted, aiming at a better understanding of the mechanism of action of this new natural product. The objectives of the present study will be to understand the mechanisms of molecular interaction of pradimicin-IRD with DNA through different methods of analysis, and the study of genes related to DNA repair pathways and silencing of selected genes as a result of treatment with pradimicin- IRD and assessment of pradimicin-IRD sensitivity in the Knockout or Knockdown cell line for genes identified as relevant during drug treatment. Therefore, we intend to contribute to the understanding of the antitumor potential of this class of molecules, from the description of its effect on the DNA, searching the understanding of the type of DNA damage through the repair systems activated by pradimicin-IRD. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DE ALMEIDA, LARISSA COSTA; BAUERMEISTER, ANELIZE; REZENDE-TEIXEIRA, PAULA; DOS SANTOS, EVELYNE ALVES; BERALDO DE MORAES, LUIZ ALBERTO; MACHADO-NETO, JOAO AGOSTINHO; COSTA-LOTUFO, LETICIA VERAS. Pradimicin-IRD exhibits antineoplastic effects by inducing DNA damage in colon cancer cells. Biochemical Pharmacology, v. 168, p. 38-47, OCT 2019. (17/17648-4, 15/17177-6, 18/17595-0, 17/24993-0, 14/50926-0)

DE ALMEIDA, LARISSA COSTA; CALIL, FELIPE ANTUNES; MORENO, NATALIA CESTARI; REZENDE-TEIXEIRA, PAULA; DE MORAES, LUIZ ALBERTO BERALDO; JIMENEZ, PAULA CHRISTINE; MENCK, CARLOS FREDERICO MARTINS; MACHADO-NETO, JOAO AGOSTINHO; COSTA-LOTUFO, LETICIA VERAS. Exploring pradimicin-IRD antineoplastic mechanisms and related DNA repair pathways. Chemico-Biological Interactions, v. 371, p. 10-pg., 2023-01-14. (17/24993-0, 18/17595-0, 14/50926-0, 19/23864-7, 21/11606-3, 19/19435-3, 15/17177-6)

MARIACATERINA LIANZA; MARIA HELENA VERDAN; JEAN PAULO DE ANDRADE; FERRUCCIO POLI; LARISSA C. DE ALMEIDA; LETICIA V. COSTA-LOTUFO; ÁLVARO CUNHA NETO; SARAH C. C. OLIVEIRA; JAUME BASTIDA; ANDREA N. L. BATISTA; et al. Isolation, Absolute Configuration and Cytotoxic Activities of Alkaloids from Hippeastrum goianum (Ravenna) Meerow (Amaryllidaceae). Journal of the Brazilian Chemical Society, v. 31, n. 10, p. 2135-2145, 2020-10-09. (14/25222-9, 18/17595-0, 15/17177-6, 14/50926-0)

DE ALMEIDA, LARISSA COSTA; CARLOS, JORGE ANTONIO ELIAS GODOY; REZENDE-TEIXEIRA, PAULA; MACHADO-NETO, JOAO AGOSRINHO; COSTA-LOTUFO, LETICIA VERAS. AD80, a multikinase inhibitor, as a potential drug candidate for colorectal cancer therapy. Life Sciences, v. 308, p. 9-pg., 2022-09-02. (18/19372-9, 17/24993-0, 18/17595-0, 19/23864-7, 21/11606-3, 15/17177-6)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ALMEIDA, Larissa Costa de. Study of pradimicin-IRD molecular interaction with DNA and its tumor cell mechanism of action.. 2022. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.