RESUMO
Breast cancer stands as one of the foremost cause of cancer-related deaths globally, characterized by its varied molecular subtypes. Each subtype requires a distinct therapeutic strategy. Although advancements in treatment have enhanced patient outcomes, significant hurdles remain, including treatment toxicity and restricted effectiveness. Here, we explore the anticancer potential of novel 1,4-naphthoquinone/4-quinolone hybrids on breast cancer cell lines. The synthesized compounds demonstrated selective cytotoxicity against Luminal and triple-negative breast cancer (TNBC) cells, which represent the two main molecular types of breast cancer that depend most on cytotoxic chemotherapy, with potency comparable to doxorubicin, a standard chemotherapeutic widely used in breast cancer treatment. Notably, these derivatives exhibited superior selectivity indices (SI) when compared to doxorubicin, indicating lower toxicity towards non-tumor MCF10A cells. Compounds 11a and 11b displayed an improvement in IC50 values when compared to their precursor, 1,4-naphthoquinone, for both MCF-7 and MDA-MB-231 and a comparable value to doxorubicin for MCF-7 cells. Also, their SI values were superior to those seen for the two reference compounds for both cell lines tested. Mechanistic studies revealed the ability of the compounds to induce apoptosis and inhibit clonogenic potential. Additionally, the irreversibility of their effects on cell viability underscores their promising therapeutic utility. In 3D-cell culture models, the compounds induced morphological changes indicative of reduced viability, supporting their efficacy in a more physiologically relevant model of study. The pharmacokinetics of the synthesized compounds were predicted using the SwissADME webserver, indicating that these compounds exhibit favorable drug-likeness properties and potential as antitumor agents. Overall, our findings underscore the promise of these hybrid compounds as potential candidates for breast cancer chemotherapy, emphasizing their selectivity and efficacy.
Assuntos
Antineoplásicos , Neoplasias da Mama , Naftoquinonas , Humanos , Naftoquinonas/farmacologia , Naftoquinonas/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Células MCF-7 , Quinolonas/farmacologia , Quinolonas/química , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células em Três Dimensões/métodos , Doxorrubicina/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacosRESUMO
Rivaroxaban (RVX), an oral direct factor Xa inhibitor, is being explored as an alternative to traditional anticoagulans. However, RVX still faces pharmacokinetic limitations and adverse effects, highlighting the need for more effective formulations. In this regard, pharmaceutical nanotechnology, particularly the use of polymeric nanoparticles (PNPs), offers a promising approach for optimizing RVX delivery. This study aimed to develop and physicochemically characterize RVX-loaded poly(lactic-co-glycolic acid) (PLGA)/sodium lauryl sulfate (SLS) or didodecyl dimethylammonium bromide (DMAB) nanoparticles, and also evaluate their pharmacological and toxicological profiles as a potential therapeutic strategy. The PNPs exhibited sizes below 300 nm and spherical morphology, with both negative and positive surface charges, according to surfactant used. They demonstrated high encapsulation efficiency and suitable yields, as well as rapid initial liberation followed by sustained release in different pH environments. Importantly, in vivo evaluations revealed a time-dependent antithrombotic effect surpassing the free form of RVX when administered orally in SLS or DMAB PNP. No hemolytic or cytotoxic effects were observed at various concentrations of the PNPs. Interestingly, the PNPs did not induce hemorrhagic events or cause liver enzyme alterations in vivo. These findings suggest that RVX-loaded SLS or DMAB PNPs are promising innovative therapeutic alternatives for the treatment of thromboembolic diseases.
Assuntos
Nanopartículas , Ácido Poliglicólico , Ratos , Animais , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Ratos Wistar , Ácido Poliglicólico/química , Dodecilsulfato de Sódio , Rivaroxabana , Brometos , Fibrinolíticos/farmacologia , Ácido Láctico/química , Glicóis , Nanopartículas/química , Tamanho da PartículaRESUMO
Phytochemicals and their metabolites are not considered essential nutrients in humans, although an increasing number of well-conducted studies are linking their higher intake with a lower incidence of non-communicable diseases, including cancer. This review summarizes the current findings concerning the molecular mechanisms of bioactive compounds from grapes and red wine and their metabolites on breast cancer-the most commonly occurring cancer in women-chemoprevention and treatment. Flavonoid compounds like flavonols, monomeric catechins, proanthocyanidins, anthocyanins, anthocyanidins and non-flavonoid phenolic compounds, such as resveratrol, as well as their metabolites, are discussed with respect to structure and metabolism/bioavailability. In addition, a broad discussion regarding in vitro, in vivo and clinical trials about the chemoprevention and therapy using these molecules is presented.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/prevenção & controle , Fitoterapia , Vitis/química , Vinho/análise , Anticarcinógenos/química , Anticarcinógenos/farmacologia , Neoplasias da Mama/metabolismo , Quimioprevenção , Feminino , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Técnicas In Vitro , Estrutura Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polifenóis/química , Polifenóis/farmacologia , Polifenóis/uso terapêuticoRESUMO
This review aims to explore the potential of resveratrol, a polyphenol stilbene, and beta-lapachone, a naphthoquinone, as well as their derivatives, in the development of new drug candidates for cancer. A brief history of these compounds is reviewed along with their potential effects and mechanisms of action and the most recent attempts to improve their bioavailability and potency against different types of cancer.
Assuntos
Antineoplásicos/farmacologia , Naftoquinonas/farmacologia , Antineoplásicos/química , Humanos , Concentração Inibidora 50 , Naftoquinonas/química , Naftoquinonas/uso terapêutico , Neoplasias/tratamento farmacológico , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Proteína Supressora de Tumor p53/metabolismoRESUMO
Dysfunctional p53 formation and activity can result from aberrant expression and subcellular localization of distinct p53 isoforms or aggregates. Endometrial carcinoma (EC) is a cancer type in which p53 status is correlated with prognosis, and TP53 mutations are a frequent genetic modification. Here we aimed to evaluate the expression patterns of different p53 isoforms and their contributions to the formation and subcellular localization of p53 amyloid aggregates in both EC and endometrial nontumor cell lines. We found that full-length (fl) p53 and a truncated p53 isoform, Δ40p53, resulting from alternative splicing of exon 2 or alternative initiation of translation at ATG-40, are the predominantly expressed p53 variants in EC cells. However, Δ40p53 was the major p53 isoform in endometrial nontumor cells. Immunofluorescence assays revealed that Δ40p53 is mainly localized to cytoplasmic punctate structures of EC cells, resembling solid-phase structures similar to those found in neurodegenerative pathologies. Using light-scattering kinetics, CD, and transmission EM, we noted that the p53 N-terminal transactivation domain significantly reduces aggregation of the WT p53 DNA-binding domain, confirming the higher aggregation tendency of Δ40p53, which lacks this domain. This is the first report of cytoplasmic Δ40p53 in EC cells being a major component of amyloid aggregates. The differential aggregation properties of p53 isoforms in EC cells may open up new avenues in the development of therapeutic strategies that preferentially target specific p53 isoforms to prevent p53 amyloid aggregate formation.
Assuntos
Amiloide/química , Amiloidose , Neoplasias do Endométrio/patologia , Agregados Proteicos , Ativação Transcricional , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo , Processamento Alternativo , Proteínas Amiloidogênicas/genética , Proteínas Amiloidogênicas/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Feminino , Humanos , Conformação Proteica , Isoformas de Proteínas , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genéticaRESUMO
p53 is a critical tumor suppressor that functions as a transcription factor. Mutations in the TP53 gene are observed in more than 50% of cancer cases worldwide. Several of these mutations lead to a less stable, aggregation-prone protein that accumulates in cancer cells. These mutations are associated with a gain of oncogenic function, which leads to cancer progression. p53 amyloid aggregation is a common feature in most of these mutants; thus, it can be used as a druggable target to reactivate or induce the degradation of p53 and promote a retraction in the aggressive pattern of mutant p53-containing cells. We show here a series of experiments for the screening and validation of new p53 antiamyloid compounds.
Assuntos
Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas Mutantes , Dobramento de Proteína , Proteína Supressora de Tumor p53/química , Antineoplásicos/farmacologia , Proliferação de Células , Citometria de Fluxo , Humanos , Cinética , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica , Dobramento de Proteína/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Overexpression of the Saccharomyces cerevisiae ABC transporter Pdr5p confers resistance to a range of structurally unrelated xenobiotics. This property allows Pdr5p to be used as a target for novel multidrug resistance reversal reagents or chemosensitizers. Herein, we report the effects of gallic acid derivatives with substitutions either on the ester moiety or in the benzene ring on the activity of Pdr5p. Compounds with a longer side chain (8-16 carbons) resulted in greater inhibition of Pdr5p ATPase. Derivatives with side chains of 8-12 carbons that retained hydroxyl groups on the benzene ring extensively inhibited Pdr5p ATPase activity. These compounds almost completely inhibited the efflux of the Pdr5p fluorescent substrate Rhodamine 6G and at 25 muM chemosensitized the Pdr5p-overexpressing strain AD124567 to fluconazole (0.4 mg mL(-1)). Gallic acid derivatives may be a new class of Pdr5p inhibitors.