RESUMO
Breast cancer is the most common cancer in women, the so-called "Triple-Negative Breast Cancer" (TNBC) subtype remaining the most challenging to treat, with low tumor-free survival and poor clinical evolution. Therefore, there is a clear medical need for innovative and more efficient treatment options for TNBC. The aim of the present study was to evaluate the potential therapeutic interest of the association of the tumor-penetrating BR2 peptide with monophosphoester 2-aminoethyl dihydrogen phosphate (2-AEH2P), a monophosphoester involved in cell membrane turnover, in TNBC. For that purpose, viability, migration, proliferative capacity, and gene expression analysis of proteins involved in the control of proliferation and apoptosis were evaluated upon treatment of an array of TNBC cells with the BR2 peptide and 2-AEH2P, either separately or combined. Our data showed that, while possessing limited single-agent activity, the 2-AEH2P+BR2 association promoted significant cytotoxicity in TNBC cells but not in normal cells, with reduced proliferative potential and inhibition of cell migration. Mechanically, the 2-AEH2P+BR2 combination promoted an increase in cells expressing p53 caspase 3 and caspase 8, a reduction in cells expressing tumor progression and metastasis markers such as VEGF and PCNA, as well as a reduction in mitochondrial electrical potential. Our results indicate that the combination of the BR2 peptide with 2-AEH2P+BR2 may represent a promising therapeutic strategy in TNBC with potential use in clinical settings.
RESUMO
Triple-negative breast cancer is the most aggressive subtype of breast cancer, with worse clinical evolution and tumor-free survival, leading to the need to develop new effective therapies for its control. The present study evaluated the action of tumor-penetrating peptide BR2 associated with 2-aminoethyl dihydrogen phosphate (2-AEH2P) on triple-negative breast tumor cells. Cell viability was evaluated by the MTT colorimetric method, mitochondrial electrical potential, and proteins involved in cell proliferation and death control were evaluated by flow cytometry and structural and morphological analysis by confocal microscopy. The results obtained showed that the peptide BR2 and the association 2-AEH2P + BR2 promoted significant cytotoxicity in tumor lines, compared to 2-AEH2P alone. In addition, the association 2-AEH2P + BR2 promoted tumor cells arrest in the G0/G1 phases. Interestingly, both treatments modulated the expression of markers CD44, CD34, CD24, cyclin D1, and Bcl-2, increased p21, Bax, and released cytochrome c. The association proved to be more effective, providing modulation of proteins involved in cell death and senescence, more pronounced cytotoxicity for tumor cells compared to normal cells, and the reduction of markers related to aggressiveness profile, progression, and tumor metastasis.