Background/Objectives: This study engineered and evaluated a targeted, folate-functionalized chitosan nanoparticle (CS-FA NP) delivery system to enhance the therapeutic efficacy of standard quercetin and Coriandrum sativum seed extract against breast cancer. Methods: Phytochemical profiling confirmed a 14% crude yield for the methanolic extract, with gas chromatography–mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC) identifying quercetin as the principal bioactive agent. The synthesized CS-FA NPs exhibited a core size of 7–20 nm, an average hydrodynamic diameter of 150–160 nm, a stable zeta potential of −55 mV, and high encapsulation efficiencies (87.2% for quercetin and 80.5% for coriander). Kinetic assessments confirmed a biphasic, diffusion-controlled release matching Higuchi matrix kinetics. Anticancer activity was evaluated in vitro using MTT cytotoxicity, Annexin V-FITC/PI apoptosis analysis, RT-qPCR, and ex vivo rat aortic ring assays, followed by validation in a syngeneic 4T1 mammary tumor mouse model. Results: In vitro, folate-receptor-targeted quercetin nanoparticles (T4) demonstrated superior, selective cytotoxicity, particularly against triple-negative MDA-MB-231 cells, while sparing normal fibroblasts. Annexin V-FITC/PI apoptosis profiling and ex vivo aortic ring assays revealed profound, cell-line-dependent programmed cell death and up to 90% inhibition of microvessel sprout outgrowth. Mechanistically, RT-qPCR verified that nano-formulations induced complete transcriptional silencing of NANOG, MMP-1, VEGFA, TSPAN8, TWIST, EMMPRIN, and CDK1, alongside marked upregulation of P27KIP1 and P21CIP1. In vivo, these nano-formulations successfully improved tumor-associated pathological features, reduced aggressive tumor spindle-cell proliferation, and suppressed elevated serum CA15-3 and arginase biomarkers. Conclusions: Folate-functionalized chitosan nano-formulations significantly enhanced the anticancer efficacy of quercetin and Coriandrum sativum seed extract through improved targeted delivery, potent antiproliferative, anti-angiogenic, and pro-apoptotic activities, together with favorable modulation of multiple molecular pathways associated with breast cancer progression. These findings support their potential as promising targeted nanotherapeutic strategies for breast cancer treatment.
Nariman Nabil, Hussein Sabit, J. Almulhim et al.· Pharmaceuticals· 0 citations
Adipose tissue, once considered a passive fuel store, is now recognized as a dynamic endocrine organ that shapes cancer behavior. Within the tumor microenvironment (TME), cancer-associated adipocytes (CAAs) undergo marked reprogramming—losing large lipid droplets, adopting fibroblast-like features, and intensifying lipolysis—while releasing proinflammatory mediators that accelerate proliferation, invasion, and therapy resistance. This interaction is bidirectional: through cytokines, adipokines, and extracellular vesicles (including exosomal microRNAs), CAAs coordinate immune recruitment, extracellular matrix (ECM) remodeling, and angiogenesis. Mechanistically, several pathways converge at this interface. YAP/TAZ, STAT3, and PI3K/AKT integrate mechanical stress, inflammatory tone, and nutrient cues; metabolic symbiosis—enhanced fatty acid oxidation alongside glycolytic rewiring—supplies energy and redox support. CAAs also amplify metastasis and chemoresistance, particularly in triple-negative breast (TNBC) and pancreatic cancers, via effectors such as CXCL8, FAM3C, and SAA1. Systemic axes also matter in cancer cachexia, adipocyte-derived lipocalin-2 (LCN2) promotes tissue wasting and dampens thermogenesis, while obesity’s chronic inflammation further biases the TME toward tumor promotion. This review synthesizes how CAAs and adipose dynamics drive oncogenesis, progression and therapeutic failure and highlights actionable nodes within the adipose–tumor axis for precision oncology.
Jinmin Shi, S. Abdel-Ghany, Mariam M Abdelfattah et al.· Signal Transduction and Targ...· 0 citations
Triple-negative breast cancer (TNBC) is an aggressive and clinically heterogeneous breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression, limited targeted treatment options, early relapse, and frequent development of therapy resistance. Although TNBC often shows initial sensitivity to chemotherapy, durable responses are commonly undermined by the emergence of adaptive resistant cell states rather than solely by fixed genetic mutations. This review synthesizes the role of epigenetic plasticity as a central mechanism that enables TNBC cells to dynamically reprogram transcriptional identity, survive therapeutic stress, and transition between epithelial, mesenchymal, stem-like, immune-evasive, and drug-tolerant persister phenotypes. Key epigenetic mechanisms include aberrant DNA methylation, histone acetylation and methylation, BET/BRD4-dependent transcriptional regulation, EZH2-mediated repression, SWI/SNF-dependent chromatin remodeling, non-coding RNA networks, and three-dimensional genome reorganization. These processes regulate tumor suppressor silencing, DNA-damage repair, epithelial–mesenchymal plasticity, cancer stem-cell maintenance, metabolic adaptation, immune-checkpoint regulation, and minimal residual disease. The review also highlights the translational relevance of epigenetic biomarkers, including DNA methylation signatures, circulating epigenetic markers, chromatin-accessibility profiles, and single-cell epigenomic approaches for diagnosis, prognosis, therapy prediction, and monitoring resistance evolution. Finally, therapeutic strategies targeting epigenetic plasticity are discussed, including DNMT, HDAC, BET, EZH2, KDM, and LSD1 inhibitors, with emphasis on rational combination approaches involving chemotherapy, PARP inhibitors, immunotherapy, and metabolic targeting. Overall, epigenetic plasticity represents both a major driver of TNBC resistance and a therapeutically exploitable vulnerability, provided those future strategies account for tumor heterogeneity, adaptive cell-state transitions, biomarker-guided patient selection, and combination-based treatment design.
A. Alaa, Salma A. B. El-Din, Mohannad A. Farrag et al.· Biomedicines· 0 citations
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