Identification of putative Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) dual inhibitors for triple-negative breast cancer therapy

Journal of Biomolecular Structure and Dynamics, Год журнала: 2025, Номер unknown, С. 1 - 19

Опубликована: Янв. 24, 2025

Tryptophan catabolism is a central pathway in many cancers, serving to sustain an immunosuppressive microenvironment. The key enzymes involved this tryptophan metabolism such as indoleamine 2,3-dioxygenase 1 (IDO1) and (TDO) are reported promising novel targets cancer immunotherapy. IDO1 TDO overexpression TNBC cells promote resistance cell death, proliferation, invasion, metastasis. To date, there no clinically available small-molecule inhibitors that target these enzymes. Navoximod, reliable dual-specific inhibitor, resulted poor bioavailability modest efficacy clinical trials restricts its utility. This situation urges the development of potent drug-like candidate against A total 1574 natural compounds were proclaimed subjected ADME screening. Subsequently, resultant attributed hierarchical molecular docking MM-GBSA validation. Ultimately, re-scoring with aid combined machine learning algorithms six lead compounds. Captivatingly, NPACT00380 exhibited maximum interaction among In addition, scaffold analysis also highlighted chromanone moiety hit compound boasts anti-cancer activity breast lines. reliability results was corroborated through rigorous 100 ns dynamics simulation using parameters including RMSD, PCA FEL analysis. light findings, it presumed proposed exhibits significant inhibitory activity. As result, we speculate further optimisation could be beneficial for treatment management TNBC.

Язык: Английский

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Platinum(IV) Complexes as Inhibitors of STAT3 and Regulators of the Tumor Microenvironment To Control Breast Cancer

Journal of Medicinal Chemistry, Год журнала: 2023, Номер 66(16), С. 11351 - 11364

Опубликована: Авг. 14, 2023

Interplay between breast cancer (BC) cells and the tumor microenvironment (TME) influences outcome of treatment. Aberrant activation signal transducer activator transcription 3 (STAT3) promotes interaction causes immunosuppression drug resistance. Platinum(IV) complexes SPP DPP bearing pterostilbene-derived axial ligand(s) were synthesized to inhibit JAK2-STAT3 pathway in BC regulate TME. These exerted remarkable antiproliferative activity against triple-negative cells, suppressed expression phosphorylated STAT3 STAT3-related cyclooxygenase-2 IL-6, activated caspase-3 cleaved poly ADP-ribose polymerase, preventing repair DNA lesions inducing apoptosis. Furthermore, promoted maturation antigen presentation dendritic repressed proliferation differentiation myeloid-derived suppressor regulatory T facilitated expansion cells. As a consequence, showed excellent anticancer with almost no general toxicity vivo as potential chemoimmunotherapeutic agent.

Язык: Английский

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Triple Negative Breast Cancer: Molecular Subtype-Specific Immune Landscapes with Therapeutic Implications

Cancers, Год журнала: 2024, Номер 16(11), С. 2094 - 2094

Опубликована: Май 31, 2024

Triple Negative Breast Cancer (TNBC) is characterized by distinct molecular subtypes with unique biological and clinical features. This systematic review aimed to identify articles examining the differences in tumor immune microenvironment (TIME) across different TNBC subtypes. Six studies meeting inclusion criteria were analyzed, utilizing gene expression profiling bioinformatic analyses classify samples into subtypes, as well immunohistochemistry cell deconvolution methods characterize TIME. Results revealed significant heterogeneity composition among immunomodulatory (IM) subtype demonstrating robust infiltration, composed mainly of adaptive cells along an increased density CTLA-4+ PD-1+ TILs, high PD-L1 expression, upregulation FOXP3+ Tregs. A more immunosuppressive TIME a predominance innate lower levels tumor-infiltrating lymphocytes (TILs) was observed luminal androgen receptor (LAR) tumors. In mesenchymal stem-like (MSL) tumors, cells, number M2 tumor-associated macrophages (TAMs), while BL M tumors displayed poor responses, indicating “immune-cold” phenotype. Differential activation signaling pathways, genomic diversity, metabolic reprogramming identified contributors heterogeneity. Understanding this interplay crucial for tailoring therapeutic strategies, especially regarding immunotherapy.

Язык: Английский

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CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid β-oxidation in triple-negative breast cancer

Cancer Letters, Год журнала: 2024, Номер 587, С. 216724 - 216724

Опубликована: Фев. 17, 2024

Язык: Английский

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The Molecular Mechanisms behind Advanced Breast Cancer Metabolism: Warburg Effect, OXPHOS, and Calcium

Frontiers in Bioscience-Landmark, Год журнала: 2024, Номер 29(3)

Опубликована: Март 13, 2024

Altered metabolism represents a fundamental difference between cancer cells and normal cells. Cancer have unique ability to reprogram their by deviating reliance from primarily oxidative phosphorylation (OXPHOS) glycolysis, in order support survival. This metabolic phenotype is referred as the “Warburg effect” associated with an increase glucose uptake, diversion of glycolytic intermediates alternative pathways that anabolic processes. These processes include synthesis nucleic acids, lipids, proteins, necessary for rapidly dividing cells, sustaining growth, proliferation, capacity successful metastasis. Triple-negative breast (TNBC) one most aggressive subtypes cancer, poorest patient outcome due its high rate TNBC characterized elevated glycolysis certain instances, low OXPHOS. dysregulation linked chemotherapeutic resistance research models samples. There more than single mechanism which this switch occurs here, we review current knowledge relevant molecular mechanisms involved advanced metabolism, focusing on TNBC. Warburg effect, adaptations, microRNA regulation, mitochondrial involvement, calcium signaling, recent player JAK/STAT signaling. In addition, explore some drugs compounds targeting reprogramming. Research these highly promising could ultimately offer new opportunities development innovative therapies treat dysregulated metabolism.

Язык: Английский

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ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 21, 2025

Triple-negative breast cancer (TNBC), lacking expression of estrogen, progesterone, and HER2 receptors, is aggressive lacks targeted treatment options. An RNA editing enzyme, adenosine deaminase acting on 1 (ADAR1), has been shown to play important roles in TNBC tumorigenesis. We posit that ADAR1 functions as a homeostatic factor protecting from internal external pressure, including metabolic stress. tested the hypothesis iron- dependent cell death pathway, ferroptosis, ADAR1-protected vulnerability by showing knockdown sensitizes cells GPX4 inhibitors. By performing single-reaction monitoring-based liquid chromatography coupled mass spectrometry (LC-MS) measure intracellular lipid contents, we showed loss increased abundance polyunsaturated fatty acid phospholipids (PUFA-PL), which peroxidation primary driver ferroptosis. Transcriptomic analyses led discovery proto-oncogene MDM2 contributing remodeling upon loss. A phenotypic drug screen using ferroptosis-focused library was performed identify FDA- approved cobimetinib drug-repurposing candidate synergize with suppress demonstrating regulates fitness through desensitizing aim leverage this inform basic, pre-clinical, clinical studies develop novel therapeutic strategies for TNBC.

Язык: Английский

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Identification of intratumoral bacteria that enhance breast tumor metastasis

mBio, Год журнала: 2025, Номер unknown

Опубликована: Фев. 11, 2025

ABSTRACT The central, mortality-associated hallmark of cancer is the process metastasis. It increasingly recognized that bacteria influence multiple facets progression, but extent to which tumor microenvironment-associated control metastasis in poorly understood. To identify tumor-associated and their role metastasis, we utilized established murine models non-metastatic metastatic breast tumors capable driving disease. We found several species Bacillus genus were unique tumors, cells cultured with a bacterium isolated from thermoamylovorans , produced nearly 3× burden as or tumors. then performed targeted metabolomics on different bacterial B. differentially regulated cell metabolite profiles compared Using these bacteria, de novo sequencing tested for presence genes patient population provide proof-of-concept identifying how specific functions are associated independent species. Together, our data directly demonstrate ability promote through interaction cells. IMPORTANCE Metastasis major barrier long-term survival patients, therapeutic options patients aggressive, forms remain limited. therefore critical understand differences between disease potential methods slowing even stopping In this work, present increasing capabilities sequenced well failed identified metastasis-promoting samples they more likely be mortality. also enrichment functions, providing insight into possible sources bacteria-driven increases types.

Язык: Английский

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Nidogen-1 suppresses cell proliferation, migration, and glycolysis via integrin β1-mediated HIF-1α downregulation in triple-negative breast cancer

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 27, 2025

Nidogen-1 (NID1) is a secreted glycoprotein widely distributed in basement membranes. NID1 interacts with extracellular matrix proteins such as collagen and laminin has been implicated the progression of various cancers. However, study on role breast cancer scarce inconsistent. In this work, we found that expression significantly lower tissue than normal tissue. addition, correlated negatively poor prognosis for patients. Based those findings, speculated might act suppressor cancer. To investigate cancer, constructed NID1-overexpressing cell lines. overexpression decreased proliferation, migration, vivo tumor growth. Moreover, glucose metabolism, which known to enhance proliferation was also by overexpression. Mechanistically, downregulated hypoxia-inducible factor-1α (HIF-1α) at transcription level. Furthermore, reduced integrin β1 stability HIF-1α through FAK/Src/NF-κB p65 signaling axis, downstream β1. Together, results demonstrate suppressive triple-negative

Язык: Английский

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Identification of a novel inflammation-related gene signature for predicting inflammatory breast cancer survival

Genome Instability & Disease, Год журнала: 2023, Номер 4(3), С. 154 - 175

Опубликована: Июнь 13, 2023

Язык: Английский

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The crucial role of fascin-1 in the pathogenesis, metastasis, and chemotherapeutic resistance of breast cancer

Pathology - Research and Practice, Год журнала: 2024, Номер 254, С. 155079 - 155079

Опубликована: Янв. 4, 2024

Язык: Английский

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