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Finding New Molecular Targets of Two Copper(II)-Hydrazone Complexes on Triple-Negative Breast Cancer Cells Using
Lucia M Balsa1, María R Rodriguez1, Verónica Ferraresi-Curotto2
1CEQUINOR (UNLP, CCT-CONICET La Plata, Asociado a CIC), Departamento de Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata 1900, Argentina.
Abstract:
Breast cancer is the most common cancer in women, with a high incidence estimated to reach 2.3 million by 2030. Triple-Negative Breast Cancer (TNBC) is the greatest invasive class of breast cancer with a poor prognosis, due to the side-effects exerted by the chemotherapy used and the low effectivity of novel treatments. In this sense, copper compounds have shown to be potentially effective as antitumor agents, attracting increasing interest as alternatives to the usually employed platinum-derived drugs. Therefore, the aim of this work is to identify differentially expressed proteins in MDA-MB-231 cells exposed to two copper(II)-hydrazone 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. Both copper complexes increased proteins involved in endoplasmic reticulum stress and unfolded protein response, as well as the downregulation 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 gain-of-function-mutant p53. Moreover, we found a novel and interesting effect for a copper metallodrug, which was the down-regulation of proteins related to lipid synthesis and metabolism that could lead to a beneficial decrease in lipid levels.
Insights
Copper compounds show promise against triple-negative breast cancer (TNBC). This study identified molecular mechanisms, including endoplasmic reticulum stress and mutant p53 downregulation, revealing potential new treatments for TNBC.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Triple-Negative Breast Cancer (TNBC) presents a significant clinical challenge due to limited treatment options and poor prognosis.
- Copper compounds are emerging as potential anticancer agents, offering an alternative to conventional platinum-based chemotherapy.
Purpose of the Study:
- To investigate the molecular mechanisms of two copper(II)-hydrazone complexes against TNBC cells.
- To identify differentially expressed proteins and affected pathways using advanced proteomics and bioinformatics.
Main Methods:
- Label-free quantitative proteomics was employed to analyze protein expression changes in MDA-MB-231 cells treated with copper complexes.
- Functional bioinformatics strategies were used to elucidate the biological pathways impacted by the copper compounds.
Main Results:
- Copper complexes induced endoplasmic reticulum stress and unfolded protein response.
- Downregulation of proteins involved in DNA replication, repair, and lipid metabolism was observed.
- Significant downregulation of gain-of-function-mutant p53 was identified as a key anticancer mechanism.
Conclusions:
- Copper(II)-hydrazone complexes exhibit potent anticancer effects against TNBC by modulating key cellular pathways.
- These compounds represent a promising therapeutic strategy, potentially offering improved efficacy and reduced side effects compared to current treatments.
- The observed downregulation of lipid synthesis proteins suggests a novel therapeutic avenue for managing TNBC.
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