Derivado N-acilidrazônico (LASSBio-2029) modula a expressão de cinases mitóticas e inibe a proliferação de células MCF-7

Abstract

Breast cancer represents the leading cause of cancer death among women worldwide. Approximately 75% of all diagnosed cases are hormone-positive, which are treated with hormone therapy. However, a considerable percentage of patients are refractory or acquire resistance to drugs used in therapeutic protocols. In this scenario, it is very important to identify new substances with pharmacological potential against breast cancer. In a previous study, a series of N-acylhydrazone derivatives was synthesized, and its antiangiogenic potential was investigated. Among tested substances, 4 (LASSBio-2027, 2028, 2029, 2052) significantly inhibited neovascularization in chorion-allantoic membrane of chicken embryos. Considering that many agents with antiangiogenic activity are effective in inhibiting the proliferation of tumor cells, the present study aimed to evaluate the influence of these substances on the proliferative behavior of MCF-7 cells, which express estrogen receptors. Results from viability assays showed that LASSBio-2029 was the most active derivative. Subsequent studies revealed that this substance inhibits the proliferation of MCF-7 cells by inducing cell cycle arrest. There was a significant increase in the G2/M population in samples treated with LASSBio-2029, with a concomitant reduction in the G1 and S populations. The antiproliferative activity of LASSBio-2029 on the MCF-7 cell line was associated with its ability to modulate genes that regulate the G2/M transition and M-phase progression. In MCF-7 cultures treated with LASSBio-2029, there was a significant reduction in the expression levels of CNNB1 (cyclin B), CDK1, AURKA (Aurora A), AURKB (Aurora B) and PLK1, while the relative abundance of CDKN1A (p21) mRNA was increased in treated group. LASSBio-2029 altered the mechanics of the cell division process leading to the appearance of abnormal mitoses and apoptotic cells. The expression levels of BCL-2 were significantly downregulated in samples treated with LASSBio-2029, indicating the involvement of the intrinsic pathway in the apoptosis induction process. Thus, the data presented in the present study showed that LASSBio-2029 is a substance with promising antitumor activity.