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Anais Da Academia Brasileira de Ciencias 2024Cancer is a complex and multifactorial disease characterized by uncontrolled cell growth and is one of the main causes of death in the world. This work aimed to evaluate...
Cancer is a complex and multifactorial disease characterized by uncontrolled cell growth and is one of the main causes of death in the world. This work aimed to evaluate a small series of 10 different indole-thiosemicarbazone compounds as potential antitumor agents. This is a pioneering study. For this, the antioxidant and cytotoxic capacity against normal and tumor cells was evaluated. The results showed that the compounds were able to promote moderate to low antioxidant activity for the ABTS radical scavenging assay. ADMET in silico assays showed that the compounds exhibited good oral bioavailability. As for toxicity, they were able to promote low cytotoxicity against normal cells, in addition to not being hemolytic. The compounds showed promising in vitro antitumor activity against the T47D, MCF-7, Jurkat and DU-145 strains, not being able to inhibit the growth of the Hepg2 strain. Through this in vitro study, it can be concluded that the compounds are potential candidates for antitumor agents.
Topics: Humans; Thiosemicarbazones; Indoles; Antineoplastic Agents; Antioxidants; Cell Line, Tumor; Computer Simulation; Drug Screening Assays, Antitumor; Cell Proliferation
PubMed: 38865509
DOI: 10.1590/0001-3765202420230811 -
Bioscience Reports Jun 2024Tamoxifen (TAM) is a key player in estrogen receptor-positive (ER+) breast cancer (BC), however, ~30% of patients experience relapse and a lower survival rate due to TAM...
Tamoxifen (TAM) is a key player in estrogen receptor-positive (ER+) breast cancer (BC), however, ~30% of patients experience relapse and a lower survival rate due to TAM resistance. TAM resistance was related to the over expression of SOX-2 gene, which is regulated by the E2F3 transcription factor in the Wnt signaling pathway. It was suggested that SOX-2 overexpression was suppressed by dexamethasone (DEX), a glucocorticoid commonly prescribed to BC patients. The aim of the present study is to explore the effect of combining DEX and TAM on the inhibition of TAM-resistant LCC-2 cells (TAMR-1) through modulating the E2F3/SOX-2-mediated Wnt signaling pathway. The effect of the combination therapy on MCF-7 and TAMR-1 cell viability was assessed. Drug interactions were analyzed using CompuSyn and SynergyFinder softwares. Cell cycle distribution, apoptotic protein expression, gene expression levels of SOX-2 and E2F3, and cell migration were also assessed. Combining DEX with TAM led to synergistic inhibition of TAMR-1 cell proliferation and migration, induced apoptosis, reduced SOX-2 and E2F3 expression and was also associated with S and G2-M phase arrest. Therefore, combining DEX with TAM may present an effective therapeutic option to overcome TAM resistance, by targeting the E2F3/SOX-2/Wnt signaling pathway, in addition to its anti-inflammatory effect.
PubMed: 38864530
DOI: 10.1042/BSR20240367 -
Communications Biology Jun 2024Estrogen Receptor α (ERα) is a major lineage determining transcription factor (TF) in mammary gland development. Dysregulation of ERα-mediated transcriptional program...
Estrogen Receptor α (ERα) is a major lineage determining transcription factor (TF) in mammary gland development. Dysregulation of ERα-mediated transcriptional program results in cancer. Transcriptomic and epigenomic profiling of breast cancer cell lines has revealed large numbers of enhancers involved in this regulatory program, but how these enhancers encode function in their sequence remains poorly understood. A subset of ERα-bound enhancers are transcribed into short bidirectional RNA (enhancer RNA or eRNA), and this property is believed to be a reliable marker of active enhancers. We therefore analyze thousands of ERα-bound enhancers and build quantitative, mechanism-aware models to discriminate eRNAs from non-transcribing enhancers based on their sequence. Our thermodynamics-based models provide insights into the roles of specific TFs in ERα-mediated transcriptional program, many of which are supported by the literature. We use in silico perturbations to predict TF-enhancer regulatory relationships and integrate these findings with experimentally determined enhancer-promoter interactions to construct a gene regulatory network. We also demonstrate that the model can prioritize breast cancer-related sequence variants while providing mechanistic explanations for their function. Finally, we experimentally validate the model-proposed mechanisms underlying three such variants.
Topics: Humans; Enhancer Elements, Genetic; Estrogen Receptor alpha; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Transcription, Genetic; Gene Regulatory Networks; MCF-7 Cells; Promoter Regions, Genetic; Cell Line, Tumor
PubMed: 38862711
DOI: 10.1038/s42003-024-06400-5 -
Biomedicine & Pharmacotherapy =... Jul 2024Breast cancer (BC) is the most prevalent cancer among women around the world. Finding new and efficient drugs has become a crucial aspect of BC treatment. Liensinine...
Liensinine diperchlorate and artemisitene synergistically attenuate breast cancer progression through suppressing PI3K-AKT signaling and their efficiency in breast cancer patient-derived organoids.
Breast cancer (BC) is the most prevalent cancer among women around the world. Finding new and efficient drugs has become a crucial aspect of BC treatment. Liensinine diperchlorate (LIN) and artemisitene (ATT) are natural compounds with potential anti-cancer activities extracted from lotus (Nelumbo nucifera Gaertn) seeds and Artemisia annua, respectively. However, the synergistic anti-breast cancer effectiveness and mechanism of LIN and ATT remain unknown. This study intended to reveal the biological functions and underlying mechanism of combined LIN and ATT treatment in BC. Herein, we first reported that LIN and ATT synergistically mitigated the proliferation, migration as well as invasion of BC cells. Besides, LIN boosted the stimulatory effect of ATT on reactive oxygen species (ROS)-mediated apoptosis in BC cells. Interestingly, LIN and ATT synergistically attenuated the growth of BC patient-derived organoids. Moreover, LIN augmented the inhibitory efficacy of ATT on BC growth in vivo without obvious side effects. Furthermore, the inactivation of PI3K-AKT pathway and its regulated proteins contributed to the therapeutic role of LIN and ATT treatment in BC. Intriguingly, a prediction model constructed as per RNA sequencing data indicated that the combination of LIN and ATT treatment might ameliorate the prognosis of BC patients. In conclusion, our present investigation demonstrated that LIN and ATT synergistically inhibited BC cell proliferation, migration as well as invasion and enhanced ROS-mediated apoptosis via suppressing the PI3K-AKT signaling, and suggested that combining LIN and ATT treatment might be a promising choice for BC therapy.
Topics: Humans; Breast Neoplasms; Female; Proto-Oncogene Proteins c-akt; Signal Transduction; Drug Synergism; Animals; Phosphatidylinositol 3-Kinases; Cell Proliferation; Mice, Nude; Cell Line, Tumor; Apoptosis; Cell Movement; Organoids; Mice; Disease Progression; Reactive Oxygen Species; Mice, Inbred BALB C; Xenograft Model Antitumor Assays; MCF-7 Cells; Isoquinolines; Phenols
PubMed: 38861856
DOI: 10.1016/j.biopha.2024.116871 -
American Journal of Cancer Research 2024The effects of short-chain fatty acids (SCFAs) have been explored against cancer due to the crosstalk between gut microbiota alterations and the immune system as a...
The effects of short-chain fatty acids (SCFAs) have been explored against cancer due to the crosstalk between gut microbiota alterations and the immune system as a crucial role in cancer development. We evaluated the SCFAs effects in both in vitro and in vivo breast cancer models. In vitro, the SCFAs displayed contrasting effects on viability index, according to the evaluation of breast cancer cells with different phenotypes, human MCF-7, SK-BR-3, MDA-MD-231, or the mouse 4T1 lineage. Acetate displayed minimal effects at concentrations up to 100 mM. Alternatively, propionate increases or reduces cell viability depending on the concentration. Butyrate and valerate showed consistent time- and concentration-dependent effects on the viability of human or mouse breast cancer cells. The selective FFA2 4-CMTB or FFA3 AR420626 receptor agonists failed to overtake the SCFA actions, except by modest inhibitory effects on MDA-MB-231 and 4T1 cell viability. The FFA2 CATPB or FFA3 and β-hydroxybutyrate receptor antagonists lacked significant activity on human cell lines, although CATPB reduced 4T1 cell viability. Butyrate significantly affected cell morphology, clonogenicity, and migration, according to the evaluation of MDA-MB-231 and 4T1 cells. A preliminary examination of in vivo oral effects of butyrate, propionate, or valerate, dosed in prophylactic or therapeutic regimens, on several parameters evaluated in an orthotopic breast cancer model showed a reduction of lung metastasis in post-tumor induction butyrate-treated mice. Overall, the present results indicate that in vitro effects of SCFAs did not rely on FFA2 or FFA3 receptor activation, and they were not mirrored in vivo, at least at the tested conditions. Overall, the present results indicate potential in vitro inhibitory effects of SCFAs in breast cancer, independent of FFA2 or FFA3 receptor activation, and, in the metastatic breast cancer model, the butyrate-dosed therapeutic regimen reduced the number of lung metastases.
PubMed: 38859825
DOI: 10.62347/ETUQ6763 -
Toxicology Jun 2024Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely...
Next Generation Risk Assessment (NGRA) is an exposure-led approach to safety assessment that uses New Approach Methodologies (NAMs). Application of NGRA has been largely restricted to assessments of consumer use of cosmetics and is not currently implemented in occupational safety assessments, e.g. under EU REACH. By contrast, a large proportion of regulatory worker safety assessments are underpinned by toxicological studies using experimental animals. Consequently, occupational safety assessment represents an area that would benefit from increasing application of NGRA to safety decision making. Here, a workflow for conducting NGRA under an occupational safety context was developed, which is illustrated with a case study chemical; sodium 2-hydroxyethane sulphonate (sodium isethionate or SI). Exposures were estimated using a standard occupational exposure model following a comprehensive life cycle assessment of SI and considering factory-specific data. Outputs of this model were then used to estimate internal exposures using a Physiologically Based Kinetic (PBK) model, which was constructed with SI specific Absorption, Distribution, Metabolism and Excretion (ADME) data. PBK modelling indicated a worst-case plasma maximum concentration (C) of 0.8 μM across the SI life cycle. SI bioactivity was assessed in a battery of NAMs relevant to systemic, reproductive, and developmental toxicity; a cell stress panel, high throughput transcriptomics in three cell lines (HepG2, HepaRG and MCF-7 cells), pharmacological profiling and specific assays relating to developmental toxicity (Reprotracker and devTOX quickPredict). Points of Departure (PoDs) for SI ranged from 104 to 5044 µM. C values obtained from PBK modelling of occupational exposures to SI were compared with PoDs from the bioactivity assays to derive Bioactivity Exposure Ratios (BERs) which demonstrated the safety for workers exposed to SI under current levels of factory specific risk management. In summary, the tiered and iterative workflow developed here represents an opportunity for integrating non animal approaches for a large subset of substances for which systemic worker safety assessment is required. Such an approach could be followed to ensure that animal testing is only conducted as a "last resort" e.g. under EU REACH.
PubMed: 38857863
DOI: 10.1016/j.tox.2024.153835 -
International Journal of Nanomedicine 2024Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized...
PURPOSE
Breast cancer is a prevalent malignancy among women worldwide, and malignancy is closely linked to the tumor microenvironment (TME). Here, we prepared mixed nano-sized formulations composed of pH-sensitive liposomes (Ber/Ru486@CLPs) and small-sized nano-micelles (Dox@CLGs). These liposomes and nano-micelles were modified by chondroitin sulfate (CS) to selectively target breast cancer cells.
METHODS
Ber/Ru486@CLPs and Dox@CLGs were prepared by thin-film dispersion and ethanol injection, respectively. To mimic actual TME, the in vitro "condition medium of fibroblasts + MCF-7" cell model and in vivo "4T1/NIH-3T3" co-implantation mice model were established to evaluate the anti-tumor effect of drugs.
RESULTS
The physicochemical properties showed that Dox@CLGs and Ber/Ru486@CLPs were 28 nm and 100 nm in particle size, respectively. In vitro experiments showed that the mixed formulations significantly improved drug uptake and inhibited cell proliferation and migration. The in vivo anti-tumor studies further confirmed the enhanced anti-tumor capabilities of Dox@CLGs + Ber/Ru486@CLPs, including smaller tumor volumes, weak collagen deposition, and low expression levels of α-SMA and CD31 proteins, leading to a superior anti-tumor effect.
CONCLUSION
In brief, this combination therapy based on Dox@CLGs and Ber/Ru486@CLPs could effectively inhibit tumor development, which provides a promising approach for the treatment of breast cancer.
Topics: Tumor Microenvironment; Animals; Female; Breast Neoplasms; Humans; Mice; Liposomes; MCF-7 Cells; Doxorubicin; Cell Proliferation; Mice, Inbred BALB C; NIH 3T3 Cells; Chondroitin Sulfates; Particle Size; Nanoparticle Drug Delivery System; Drug Delivery Systems; Cell Movement; Nanoparticles
PubMed: 38855730
DOI: 10.2147/IJN.S460874 -
ACS Omega Jun 2024Cancer, characterized by uncontrolled cell proliferation, remains a global health challenge. Despite advancements in cancer treatment, drug resistance and adverse...
Evaluation of Novel Spiro-pyrrolopyridazine Derivatives as Anticancer Compounds: In Vitro Selective Cytotoxicity, Induction of Apoptosis, EGFR Inhibitory Activity, and Molecular Docking Analysis.
Cancer, characterized by uncontrolled cell proliferation, remains a global health challenge. Despite advancements in cancer treatment, drug resistance and adverse effects on normal cells remain challenging. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase protein, is crucial in controlling cell proliferation and is implicated in various cancers. Here, the cytotoxic and apoptotic potential of 21 newly synthesized spiro-pyrrolopyridazine (SPP) derivatives was investigated on breast (MCF-7), lung (H69AR), and prostate (PC-3) cancer cells. XTT assay was used for cytotoxicity assessment. Flow cytometry and western blot (WB) analyses were conducted for apoptosis detection. Additionally, the EGFR inhibitory potential of these derivatives was evaluated via a homogeneous time-resolved fluorescence (HTRF) assay, and WB and molecular docking studies were conducted to analyze the binding affinities of SPP10 with EGFR. SPPs, especially SPP10, exhibit significant cytotoxicity across MCF-7, H69AR, and PC-3 cancer cells with IC values of 2.31 ± 0.3, 3.16 ± 0.8, and 4.2 ± 0.2 μM, respectively. Notably, SPP10 demonstrates selective cytotoxicity against cancer cells with a low impact on nontumorigenic cells (IC value: 26.8 ± 0.4 μM). Flow cytometric analysis demonstrated the potent induction of apoptotic cell death by SPP10 in all of the tested cancer cells. Western blot analysis revealed the involvement of key apoptotic proteins, with SPP10 notably inhibiting antiapoptotic Bcl-2 while inducing pro-apoptotic Bax and cytochrome c. SPP10 exhibited significant EGFR kinase inhibitory activity, surpassing the efficacy of the reference drug erlotinib. Molecular docking studies support these findings, revealing strong binding affinities of SPP10 with both wild-type and mutated EGFR. The study underscores the significance of heterocyclic compounds, particularly spiro-class heterocyclic molecules, in advancing cancer research. Overall, SPP10 emerges as a promising candidate for further investigations in cancer treatment, combining potent cytotoxicity, apoptotic induction, and targeted EGFR inhibition.
PubMed: 38854531
DOI: 10.1021/acsomega.4c00794 -
Nutrition Research and Practice Jun 2024Breast cancer is considered a serious health issue worldwide and is influenced by risk factors, including physical inactivity and unhealthy diet. Myokines secreted by...
BACKGROUND/OBJECTIVES
Breast cancer is considered a serious health issue worldwide and is influenced by risk factors, including physical inactivity and unhealthy diet. Myokines secreted by muscles during physical activity play a crucial role in cancer development and the immune system. Genistein (Gen), an isoflavone primarily in legumes, induces anti-cancer activity by regulating cancer stem cells (CSCs). Therefore, this study investigated the potential anti-cancer effect of a combination of myokine and Gen on the human breast cancer MCF-7 cells.
MATERIALS/METHODS
MCF-7, a human breast cancer cell line, was used for study. The cell viability of MCF-7 cells was evaluated in response to treatment with myokines, irisin (Iri), oncostatin M (OSM), and Gen using the MTT assay. Clonogenic and sphere formation assays were used to evaluate the self-renewal capacity of breast CSCs. The mRNA expression levels of stem cell markers were analyzed in MCF-7 breast cancer cells.
RESULTS
Administering Iri or OSM with Gen significantly inhibited the self-renewal capacity of MCF-7 cells. In addition, mRNA expression of breast CSC markers and , which are characteristic of CSCs, was suppressed by both myokine and Gen. However, combining Iri or OSM with Gen was the most effective treatment.
CONCLUSION
These results suggested that combining Iri or OSM with Gen has an additive effect on breast CSCs by regulating self-renewal capacity and expression of CSCs markers. Therefore, the combination of myokines and Gen may have the therapeutic potential for treating breast cancer and improving the quality of life of cancer patients.
PubMed: 38854472
DOI: 10.4162/nrp.2024.18.3.436 -
BMC Complementary Medicine and Therapies Jun 2024The historical use of Laurus nobilis L., the plant is native to the Mediterranean region and has been cultivated for its aromatic leaves, which are used as a flavoring...
BACKGROUND
The historical use of Laurus nobilis L., the plant is native to the Mediterranean region and has been cultivated for its aromatic leaves, which are used as a flavoring agent in cooking and for their potential therapeutic properties.
METHODS
The purpose of the current investigation was to characterize the essential oil composition of the fresh L. nobilis leaves from Palestine by using the gas chromatography-mass spectrometry (GC-MS) technique. DPPH (2,2-diphenyl-1-picrylhydrazyl), p-nitrophenyl butyrate, and 3,5-dinitro salicylic acid (DNSA) methods were employed to estimate the antioxidant, antiobesity, and antidiabetic effects of the essential oil. While MTS assay were used to evaluate their antiproliferative activities on panels of cell lines. Moreover, the docking studies were aided by the Prime MM GBSA method for estimating binding affinities.
RESULTS
The GC-MS investigation demonstrated that the fresh L. nobilis leaves essential oil has a variety of chemicals, about 31 different biochemicals were identified, and the major compounds were 1,8-cineole (48.54 ± 0.91%), terpinyl acetate (13.46 ± 0.34%), and α-terpinyl (3.84 ± 0.35%). Furthermore, the investigated oil demonstrated broad-spectrum antimicrobial activity against all tested bacterial and candidal strains and significantly inhibited the growth of MCF-7 cancerous cells more than the chemotherapeutic drug Doxorubicin. Furthermore, it contains robust DPPH free radicals, as well as porcine pancreatic α-amylase and lipase enzymes. Using the 1,8-cineole compound as the predominant biomolecule found in the L. nobilis essential oil, molecular docking studies were performed to confirm these observed fabulous results. The molecular docking simulations proposed that these recorded biological activities almost emanated from its high ability to form strong and effective hydrophobic interactions, this led to the getting of optimal fitting and interaction patterns within the binding sites of the applied crystallographic protein targets.
CONCLUSION
The results of these experiments showed that the fresh L. nobilis leaves essential oil has outstanding pharmacological capabilities, making this oil a potential source of natural medications.
Topics: Molecular Docking Simulation; Oils, Volatile; Plant Leaves; Humans; Laurus; Phytochemicals; Antioxidants; Middle East; Gas Chromatography-Mass Spectrometry; Cell Line, Tumor
PubMed: 38851735
DOI: 10.1186/s12906-024-04528-9