The Antitumoral/Antimetastatic Action of the Flavonoid Brachydin A in Metastatic Prostate Tumor Spheroids In Vitro Is Mediated by (Parthanatos) PARP-Related Cell Death

Autor(es)

Ribeiro, Diego Luis ; Tuttis, Katiuska ; Bastos de Oliveira, Larissa Cristina ; Serpeloni, Juliana Mara ; Faria Gomes, Izabela Natalia ; Lengert, Andre van Helvoort ; da Rocha, Claudia Quintino ; Reis, Rui Manuel ; de Syllos Colus, Ilce Mara ; Greggi Antunes, Lusania Maria

• Tipo de documento: Artigo Científico
• Fonte: PHARMACEUTICS; v. 14, n. 5, p. 20-pg., 2022-05-01.

Resumo

Metastatic prostate cancer (mPCa) is resistant to several chemotherapeutic agents. Brachydin A (BrA), a glycosylated flavonoid extracted from Fridericia platyphylla, displays a remarkable antitumoral effect against in vitro mPCa cells cultured as bidimensional (2D) monolayers. Considering that three-dimensional (3D) cell cultures provide a more accurate response to chemotherapeutic agents, this study investigated the antiproliferative/antimetastatic effects of BrA and the molecular mechanisms underlying its action in mPCa spheroids (DU145) in vitro. BrA at 60-100 mu M was cytotoxic, altered spheroid morphology/volume, and suppressed cell migration and tumor invasiveness. High-content analysis revealed that BrA (60-100 mu M) reduced mitochondrial membrane potential and increased apoptosis and necrosis markers, indicating that it triggered cell death mechanisms. Molecular analysis showed that (i) 24-h treatment with BrA (80-100 mu M) increased the protein levels of DNA disruption markers (cleaved-PARP and p-gamma-H2AX) as well as decreased the protein levels of anti/pro-apoptotic (BCL-2, BAD, and RIP3K) and cell survival markers (p-AKT1 and p-44/42 MAPK); (ii) 72-h treatment with BrA increased the protein levels of effector caspases (CASP3, CASP7, and CASP8) and inflammation markers (NF-kB and TNF-alpha). Altogether, our results suggest that PARP-mediated cell death (parthanatos) is a potential mechanism of action. In conclusion, BrA confirms its potential as a candidate drug for preclinical studies against mPCa. (AU)

• Processo FAPESP: 17/22305-9 - Estudo de biomarcadores de resposta ao cetuximabe e perspectivas do uso de combi-moléculas anti-EGFR em tumores sólidos
• Beneficiário: Izabela Natalia Faria Gomes
• Modalidade de apoio: Bolsas no Brasil - Doutorado