Anticancer mechanisms determination of N‐(o‐carboxybenzoyl)‐derived compounds of L‐amino acids serie on MDA‐MB‐231 cell line of TNBC

Abstract

Breast cancer is ranked as the second most frequent neoplasm worldwide [1], of which approximately 15% is subclassified as triple negative breast cancer (TNBC), characterized by absence of estrogen, progesterone and HER2/neu receptors. TNBC has been identified as one of the most aggressive cancers, due to its null response to endocrine therapies and trastuzumab [2]. Breast cancer is a pathology associated with aging and unhealthy lifestyles, which has been proven through studies that demonstrate MDA‐MB‐231 TNBC cells overexpress HDAC8 as a consequence of epigenetic dysregulation mechanisms linked to the high level proliferative capacity, resulting into high risk of recurrence and low survival [3]. Because all above our work group has focused in the design by Docking technique and synthesis of new HDAC inhibitor (HDACi) compounds as a therapeutic target for the TNBC. In this investigation, N‐(o‐carboxybenzoyl) derived compounds of L‐amino acids were used to determine their cytotoxicity by inhibiting the proliferation and viability of the cell line MDA‐MB‐231, as well as elucidate the possible mechanisms of cell death induced by the compounds BisLys, GlutEt and I1.MethodsTo evaluate overall cellular toxicity of BisLys, GlutEt and I1 compounds, MDA‐MB‐231 cells were seeded and incubated at 37°C in a 5% CO2, DMEM F12 medium supplemented with FBS. Compounds were added in 8 different concentrations, DMEM F12 medium was used as a negative control and SAHA as a positive control. The proliferation and viability of TNBC cells was quantified by the colorimetric for 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Type of cell death whether it was necrosis or apoptosis was determined using Annexine V and propidium iodide by flow cytometry. Finally, the blocked cell cycle progression by those compounds was determined using Cayman 10009349 Kit by flow cytometry.ResultsThe compounds BisLys and Glut Et decreased cell proliferation via apoptosis after 24h of treatment and blocked cell cycle progression at G1 phase with a concurrent decrease in S and G2/M phase. On the other hand, compound I1 did not significantly decrease cell proliferation after 24 hours of treatment. However, it shared the blocked cell cycle progression at G1 phase in the same way as the BisLys and Glut Et compounds.ConclusionCompounds BisLys and Glut Et were able to inhibit the proliferation of the MDA‐MB‐231 cell line and induced blocked cell cycle and cell death mainly by apoptosis, so they could be considered as potentially therapeutic compounds.Support or Funding InformationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.