BBIT20 inhibits homologous DNA repair with disruption of the BRCA1-BARD1 interaction in breast and ovarian cancer.
Advances in the treatment of triple-negative breast cancer (TNBC) and ovarian cancer (OC) remain challenging. In particular, resistance to the available therapy, by restoring or overexpressing the DNA repair machinery, has often been reported. New strategies to improve the therapeutic outcomes of these cancers are needed. Herein, we disclose the dregamine 5-bromo-pyridin-2-ylhydrazone (BBIT20), a natural monoterpene indole alkaloid derivative, as an inhibitor of homologous DNA repair (HDR).To unveil BBIT20 antitumor activity and underlying molecular mechanism of action, two-dimensional (2D) and three-dimensional (3D) cell cultures, patient-derived cell lines and xenograft mouse models were used.BBIT20 disrupted the BRCA1-BARD1 interaction, triggering nuclear-to-cytoplasmic BRCA1 translocation, cell cycle arrest and downregulation of HDR-related genes and proteins, with subsequent enhancement of DNA damage, reactive oxygen species generation and apoptosis, in TNBC and OC cells. BBIT20 also displayed pronounced antitumor activity in patient-derived cells and xenograft mouse models of OC, with low toxicity in non-malignant cells and undetectable side effects in mice. Additionally, it did not induce resistance in TNBC and OC and displayed marked synergistic effects with cisplatin and olaparib (a poly (ADP-ribose) polymerase inhibitor), on 2D and 3D models of these cancer cells.These findings add an inhibitor of the BRCA1-BARD1 interaction to the list of DNA-damaging agents. Importantly, either as a single agent or in combination therapy, BBIT20 reveals great potential in the personalized treatment of aggressive and resistant cancers, particularly TNBC and advanced OC.
Authors: Liliana Raimundo, Ângela Paterna, Juliana Calheiros, Joana Ribeiro, David Cardoso, Ilaria Piga, Susana Junqueira Neto, Denise Hegan, Peter M Glazer, Stefano Indraccolo, Silva Mulhovo, José Luís Costa, Maria-José U Ferreira, Lucília Saraiva