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Exploring lipid and cysteine metabolism in breast carcinoma: characterizing systemic metabolic remodeling and therapeutic response to selenium chrysin (SeChry) treatment
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Resumo: O carcinoma da mama (CM) continua a representar um grande desafio terapêutico, devido à sua heterogeneidade metabólica e à frequente resistência aos tratamentos convencionais. A presente tese explora o potencial terapêutico da modulação do metabolismo da cisteína e do metabolismo lípidico — duas vias essenciais que suportam a sobrevivência e o equilíbrio redox das células cancerígenas. Para tal, utilizámos nanopartículas de selénio-crisina funcionalizadas com folato (SeChry@PUREG4-FA₂) para inibir o transportador de cistina/glutamato (xCT) e a enzima cistationina β-sintase (CBS), bem como a arilpiperazina 5k para inibir o transportador de ácidos gordos 1 (FATP1). Avaliámos os efeitos individuais e sinérgicos destes compostos em linhas celulares luminais (MCF7 e BT-474) e triplo-negativas de CM (CMTN) (HCC1806 e MDA-MB-231).
In vitro, o SeChry@PUREG4-FA₂ reduziu a viabilidade celular de forma variável entre os subtipos celulares, tendo as linhas HCC1806 e MCF7 sido as mais sensíveis. Este composto inibiu a expressão do xCT e da CBS; e induziu alterações compatíveis com ferroptose, incluindo a depleção de gotículas lipídicas, a diminuição de ROS citoplasmáticos e a acumulação de peróxidos lipídicos. A combinação com o 5k intensificou a peroxidação lipídica, tanto nas células luminais como nas células de CMTN. A caracterização do exometaboloma revelou que o tratamento combinado afetou os metabolitos envolvidos na síntese de glutationa nas linhas celulares luminais. No modelo ex vivo de membrana corioalantóide (CAM) de embrião de galinha de CMTN, o SeChry@PUREG4-FA₂, isolado ou combinado com o 5k, reduziu a área tumoral, sem impacto significativo na densidade vascular. Num modelo murino de CMTN, a toxicidade do SeChry@PUREG4-FA₂, isolado ou combinado com o 5k foi explorada. A análise de marcadores de toxicidade em amostras séricas periféricas dos ratos não revelou toxicidade sistémica significativa associada a estes compostos.
Os nossos resultados demonstram que o SeChry@PUREG4-FA₂ é um indutor potente da ferroptose no CM. A abordagem combinatória que perturba simultaneamente o metabolismo lipídico e da cisteína apresenta-se como uma estratégia terapêutica promissora, particularmente em casos agressivos de CMTN que expressam o recetor de folato-α.
Abstract: Breast cancer (BC) remains a major therapeutic challenge due to its frequent resistance to conventional treatments, which may reside in metabolic heterogeneity. Previous work from our team has demonstrated that the cystine/glutamate antiporter (xCT) and the fatty acid transport protein 1 (FATP1) are involved in metabolic remodeling that supports BC survival and redox homeostasis by transporting cystine and fatty acids (FA), respectively. This thesis explores the therapeutic potential of targeting cysteine and FA metabolism, using a folate-functionalized nanoformulation of selenium-chrysin (SeChry@PUREG4-FA₂) to inhibit xCT and cystathionine-β-synthase (CBS), and the arylpiperazine derivative 5k to inhibit FATP1. We evaluated their individual and combined effects across luminal cell lines (MCF7 and BT-474) and triple-negative BC (TNBC) cell lines (HCC1806 and MDA-MB-231). In vitro, SeChry@PUREG4-FA₂ reduced cell viability in a subtype-dependent manner, with HCC1806 and MCF7 cell lines showing the highest sensitivity. This compound downregulated xCT and CBS expression, induced lipid droplet depletion, decreased cytoplasmic ROS, and led to a significant accumulation of lipid peroxides. The combination of SeChry@PUREG4-FA₂ with 5k further enhanced lipid peroxidation in both luminal and TNBC cells. The exometabolome profiling revealed treatment-specific rewiring, with the combined regimen profoundly perturbing metabolites involved in glutathione (GSH) synthesis in luminal cells. In a Chicken Chorioallantoic Membrane (CAM) ex vivo assay, SeChry@PUREG4-FA₂, alone or with 5k, reduced tumor area in TNBC xenografts without affecting tumor vessel density. As a complement to a TNBC murine model developed by our team, the systemic toxicity of SeChry@PUREG4-FA₂, alone or combined with 5k, was assessed using peripheral serum analyses, revealing no significant treatment-related toxicity. Our findings demonstrate that SeChry@PUREG4-FA₂ is a potent inducer of ferroptosis in BC, the efficacy of which depends on the metabolic requirements of each molecular subtype. The combinatorial approach of disrupting both cysteine and FA metabolism holds promise for overcoming therapy resistance, particularly in aggressive, folate receptor-α-positive TNBC.
Abstract: Breast cancer (BC) remains a major therapeutic challenge due to its frequent resistance to conventional treatments, which may reside in metabolic heterogeneity. Previous work from our team has demonstrated that the cystine/glutamate antiporter (xCT) and the fatty acid transport protein 1 (FATP1) are involved in metabolic remodeling that supports BC survival and redox homeostasis by transporting cystine and fatty acids (FA), respectively. This thesis explores the therapeutic potential of targeting cysteine and FA metabolism, using a folate-functionalized nanoformulation of selenium-chrysin (SeChry@PUREG4-FA₂) to inhibit xCT and cystathionine-β-synthase (CBS), and the arylpiperazine derivative 5k to inhibit FATP1. We evaluated their individual and combined effects across luminal cell lines (MCF7 and BT-474) and triple-negative BC (TNBC) cell lines (HCC1806 and MDA-MB-231). In vitro, SeChry@PUREG4-FA₂ reduced cell viability in a subtype-dependent manner, with HCC1806 and MCF7 cell lines showing the highest sensitivity. This compound downregulated xCT and CBS expression, induced lipid droplet depletion, decreased cytoplasmic ROS, and led to a significant accumulation of lipid peroxides. The combination of SeChry@PUREG4-FA₂ with 5k further enhanced lipid peroxidation in both luminal and TNBC cells. The exometabolome profiling revealed treatment-specific rewiring, with the combined regimen profoundly perturbing metabolites involved in glutathione (GSH) synthesis in luminal cells. In a Chicken Chorioallantoic Membrane (CAM) ex vivo assay, SeChry@PUREG4-FA₂, alone or with 5k, reduced tumor area in TNBC xenografts without affecting tumor vessel density. As a complement to a TNBC murine model developed by our team, the systemic toxicity of SeChry@PUREG4-FA₂, alone or combined with 5k, was assessed using peripheral serum analyses, revealing no significant treatment-related toxicity. Our findings demonstrate that SeChry@PUREG4-FA₂ is a potent inducer of ferroptosis in BC, the efficacy of which depends on the metabolic requirements of each molecular subtype. The combinatorial approach of disrupting both cysteine and FA metabolism holds promise for overcoming therapy resistance, particularly in aggressive, folate receptor-α-positive TNBC.
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Breast cancer Ferroptosis xCT Metabolomics Selenium-chrysin (SeChry) Arylpiperazine 5k