Naphthoquinone-Quinolone Hybrids with Antitumor Effects on Breast Cancer Cell Lines-From the Synthesis to 3D-Cell Culture Effects.

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.

Comparative Anticancer Potential of Green Tea Extract and Epigallocatechin-3-gallate on Breast Cancer Spheroids.

Despite advances in diagnosis and therapy, breast cancer remains the leading cause of death in many countries. Green tea (GT) has been proposed to play a crucial role in cancer chemoprevention. Although extensive research has been conducted on GT phytochemicals, most experimental studies concentrate mainly on commercial formulations or isolated catechins. This study presents a comparative investigation into the anticancer properties of green tea extract (GTE) and epigallocatechin-3-gallate (EGCG) in a three-dimensional (3D) MCF-7 breast cancer cell culture. MCF-7 spheroids were exposed to GTE or EGCG, and effects on 3D culture formation, growth, cell viability, and migration were examined. GTE inhibits cell migration and the formation of breast cancer spheroids more effectively than EGCG, while inducing more pronounced morphological changes in the spheroids' structure. These findings suggest that the food matrix improves GTE effects on breast cancer spheroids, supporting the hypothesis that a mixture of phytochemicals might enhance its anticancer potential.

Green Tea (Camellia sinensis) Extract Induces p53-Mediated Cytotoxicity and Inhibits Migration of Breast Cancer Cells.

Green tea (GT) has been shown to play an important role in cancer chemoprevention. However, the related molecular mechanisms need to be further explored, especially regarding the use of GT extract (GTE) from the food matrix. For this study, epigallocatechin gallate (EGCG) and epigallocatechin (EGC) were identified in GTE, representing 42 and 40% of the total polyphenols, respectively. MDA-MB-231 (p53-p.R280K mutant) and MCF-7 (wild-type p53) breast tumor cells and MCF-10A non-tumoral cells were exposed to GTE for 24-48 h and cell viability was assessed in the presence of p53 inhibitor pifithrin-α. GTE selectively targeted breast tumor cells without cytotoxic effect on non-tumoral cells and p53 inhibition led to an increase in viable cells, especially in MCF-7, suggesting the involvement of p53 in GTE-induced cytotoxicity. GTE was also effective in reducing MCF-7 and MDA-MD-231 cell migration by 30 and 50%, respectively. An increment in p53 and p21 expression stimulated by GTE was observed in MCF-7, and the opposite phenomenon was found in MDA-MB-231 cells, with a redistribution of mutant-p53 from the nucleus and no differences in p21 levels. All these findings provide insights into the action of GTE and support its anticarcinogenic potential on breast tumor cells.

Bioactive Compounds and Metabolites from Grapes and Red Wine in Breast Cancer Chemoprevention and Therapy.

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.

Anticancer Potential of Resveratrol, ß-Lapachone and Their Analogues.

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.

Methods to Screen Compounds Against Mutant p53 Misfolding and Aggregation for Cancer Therapeutics.

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.

Resveratrol prevents p53 aggregation in vitro and in breast cancer cells.

One potential target for cancer therapeutics is the tumor suppressor p53, which is mutated in more than 50% of malignant tumors. Loss of function (LoF), dominant negative (DN) and gain of function (GoF) mutations in p53 are associated with amyloid aggregation. We tested the potential of resveratrol, a naturally occurring polyphenol, to interact and prevent the aggregation of wild-type and mutant p53 in vitro using fluorescence spectroscopy techniques and in human breast cancer cells (MDA-MB-231, HCC-70 and MCF-7) using immunofluorescence co-localization assays. Based on our data, an interaction occurs between resveratrol and the wild-type p53 core domain (p53C). In addition, resveratrol and its derivatives pterostilbene and piceatannol inhibit mutant p53C aggregation in vitro. Additionally, resveratrol reduces mutant p53 protein aggregation in MDA-MB-231 and HCC-70 cells but not in the wild-type p53 cell line MCF-7. To verify the effects of resveratrol on tumorigenicity, cell proliferation and cell migration assays were performed using MDA-MB-231 cells. Resveratrol significantly reduced the proliferative and migratory capabilities of these cells. Our study provides evidence that resveratrol directly modulates p53, enhancing our understanding of the mechanisms involved in p53 aggregation and its potential as a therapeutic strategy for cancer treatment.

Cancer Chemoprevention by Resveratrol: The p53 Tumor Suppressor Protein as a Promising Molecular Target.

Increasing epidemiological and experimental evidence has demonstrated an inverse relationship between the consumption of plant foods and the incidence of chronic diseases, including cancer. Microcomponents that are naturally present in such foods, especially polyphenols, are responsible for the benefits to human health. Resveratrol is a diet-derived cancer chemopreventive agent with high therapeutic potential, as demonstrated by different authors. The aim of this review is to collect and present recent evidence from the literature regarding resveratrol and its effects on cancer prevention, molecular signaling (especially regarding the involvement of p53 protein), and therapeutic perspectives with an emphasis on clinical trial results to date.

Activation of Nrf2-Antioxidant Signaling by 1,25-Dihydroxycholecalciferol Prevents Leptin-Induced Oxidative Stress and Inflammation in Human Endothelial Cells.

Background: Obesity is associated with hyperleptinemia and endothelial dysfunction. Hyperleptinemia has been reported to induce both oxidative stress and inflammation by increasing reactive oxygen species production.Objective: The objective of this study was to determine the effects of 1,25-dihydroxycholecalciferol [1,25(OH)2D3] against leptin-induced oxidative stress and inflammation in human endothelial cells.Methods: Small interfering RNA (siRNA) were used to knock down the expression of vitamin D receptor (VDR) in human umbilical vein endothelial cells (HUVECs). HUVECs were pretreated for 4 h with physiologic (10-10 M) or supraphysiologic (10-7 M) concentrations of 1,25(OH)2D3 and exposed to leptin (10 ng/mL). Superoxide anion production and translocation of nuclear factor (erythroid-derived 2)-like 2 (NRF2) and nuclear transcription factor κB (NF-κB) subunit p65 to the nucleus and the activation of their target genes were quantified.Results: Pretreatment of HUVECs with 1,25(OH)2D3 prevented the leptin-induced increase in superoxide anion production (P < 0.05). Pretreatment with 1,25(OH)2D3 further increased NRF2 translocation to the nucleus (by 3-fold; P < 0.05) and increased mRNA expression of superoxide dismutase 2 (SOD2; by 2-fold), glutathione peroxidase (GPX; by 3-fold), NAD(P)H dehydrogenase (quinone) 1 (NQO1; by 4-fold), and heme oxygenase 1 (HMOX1; by 2-fold) (P < 0.05). Leptin doubled the translocation of NF-κB (P < 0.05) to the nucleus and increased (P < 0.05) the upregulation of vascular inflammatory mediators such as monocyte chemoattractant protein 1 (MCP1; by 1-fold), transforming growth factor ß (TGF ß by 1-fold), and vascular cell adhesion molecule 1 (VCAM1; by 4-fold) (P < 0.05), which were prevented (P < 0.05) by pretreatment with 1,25(OH)2D3 Protective effects of 1,25(OH)2D3 were confirmed to be VDR dependent by using VDR siRNA.Conclusion: Pretreatment with 1,25(OH)2D3 in the presence of a high concentration of leptin has a beneficial effect on HUVECs through the regulation of mediators of antioxidant activity and inflammation.