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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: Biochemical Pharmacology; v. 168, p. 38-47, OCT 2019.
• Web of Science Citations: 1

Abstract

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)

• FAPESP's process: 17/17648-4 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
• Grantee: Anelize Bauermeister
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• 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: 18/17595-0 - Study of pradimicina-IRD molecular interaction with DNA and its tumor cell mechanism of action
• Grantee: Larissa Costa de Almeida
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/24993-0 - Investigation of Stathmin 1 and microtubule instability in phenotype of hematological neoplasms
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/50926-0 - INCT 2014: biodiversity and natural products
• Grantee: Vanderlan da Silva Bolzani
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants