Finding new molecular targets of two copper(II)-hydrazones complexes on triple negative breast cancer cells using Mass Spectrometry-based Quantitative Proteomics.

BALSA, L.M.; RODRIGUEZ M.R.; FERRARESI V; BEATRIZ S. PARAJÓN COSTA; GONZALEZ BARO AG; LEON I.E

Congreso; VIII Latin American Meeting on Biological Inorganic Chemistry (LABIC); 2023

Breast cancer is the most common cancer in women, with a high incidence estimated to reach 2.3 million by 2030 [1]. Triple Negative Breast Cancer (TNBC) is the greatest invasive class of breast cancer with a poor prognosis, due to side effects exerted by chemotherapy used and the low effectivity of novel treatments [2]. In this sense, copper compounds have shown to be potentially effective as antitumor agents, attracting increasing interest as alternatives to usually employed platinum- derived drugs [3]. We have previously reported the synthesis, physicochemical characterization, and antitumoral activity of two copper(II)-hydrazones complexes, CuHL1 [4][5] and CuHL2 [6]. In vitro studies revealed promising anticancer activity of both complexes against breast cancer cell lines, including the TNBC line MDA-MB-231. However, the key signal pathways underlying the anticancer mechanism, and the therapeutic targets of CuHL1 and CuHL2 haves not yet been well characterized.Therefore, the aim of this work is to identify differentially expressed proteins in MDA-MB-231 cells exposed to two copper(II)-hydrazones complexes using label-free quantitative proteomics and functional bioinformatics strategies to identify the molecular mechanisms through which these copper complexes exert their antitumoral effect in TNBC cells. Bioinformatic and functional analysis revealed similar modes of action between both complexes. CuHL1 and CuHL2 treatment increased proteins involved in ER stress and UPR, as well as the down-regulation of proteins related to DNA replication and repair. One of the most relevant anticancer mechanisms of action found for CuHL1 and CuHL2 was the down-regulation of GOF-mutant p53. Moreover, we found a novel and interesting effect for a copper metallodrug, the down-regulation of proteins related to lipid synthesis and metabolism that could lead to a beneficial decrease in lipid levels.