Search Results (5,218)

Glioblastoma is one of the most highly aggressive types of brain tumor in adults. With limited treatment options, current therapies remain insufficient due to its invasiveness and immune evasion, highlighting the urgent need for new treatments. Bifunctional molecules targeting multiple aspects of the disease could be promising to overcome drug resistance and tumor heterogeneity. Metformin has demonstrated protective effects against brain tumors but requires high doses for efficacy, making it of great interest for molecular optimization. In this context, we synthesized a series of nine metformin–phenolic molecules, combining the metformin guanidine framework with phenolic acids, which have well-established properties in inhibiting cancer cell migration and adhesion. Their impact on cytotoxicity, reactive oxygen species inhibition, and signaling pathways was investigated for glioma cell lines and stem cells. Two of these hybrids, 5a and 5h, particularly enhanced cytotoxicity in glioblastoma cells, selectively targeting cancer cells while sparing healthy ones. Their mechanism of action differed significantly from metformin. Unlike metformin, which mainly triggers metabolic stress, the hybrids broadly inhibit RTK–MAPK–PI3K signaling, leading to cell cycle arrest and apoptosis. The results suggest that these compounds could offer a more effective and synergistic approach for glioblastoma treatment. Full article

Lung cancer remains a major public health challenge due to high incidence and mortality. The chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1) constitute a critical axis in tumor biology, influencing tumor cell proliferation, invasion, angiogenesis, and immune evasion. Aberrant CXCR4 expression is frequently observed in lung cancer and is closely associated with adverse prognosis, enhanced metastatic potential, and therapeutic resistance. Mechanistically, CXCR4 activates signaling pathways including PI3K/AKT, MAPK/ERK, JAK/STAT, and FAK/Src, promoting epithelial–mesenchymal transition, stemness, and survival. The CXCL12/CXCR4 axis also orchestrates interactions with the tumor microenvironment, facilitating chemotaxis toward CXCL12-rich niches (e.g., bone marrow and brain) and modulating anti-tumor immunity via regulatory cells. Regulation of CXCR4 occurs at transcriptional, epigenetic, and post-transcriptional levels, with modulation by hypoxia, inflammatory signals, microRNAs, and post-translational modifications. Clinically, high CXCR4 expression correlates with metastasis, poor prognosis, and reduced response to certain therapies, underscoring its potential as a prognostic biomarker and therapeutic target. Therapeutic strategies targeting CXCR4 include small-molecule antagonists (e.g., AMD3100/plerixafor; balixafortide), anti-CXCR4 antibodies, and CXCL12 decoys, as well as imaging probes for patient selection and response monitoring (e.g., 68Ga-pentixafor PET). Preclinical and early clinical studies suggest that CXCR4 blockade can impair tumor growth, limit metastatic spread, and enhance chemotherapy and immunotherapy efficacy, although hematopoietic side effects and infection risk necessitate careful therapeutic design. This review synthesizes the molecular features, regulatory networks, and translational potential of CXCR4 in lung cancer and discusses future directions for precision therapy and biomarker-guided intervention. Full article

In response to ionizing radiation (IR), both adult and cancer stem cells enter reversible cell cycle arrest at the G1/S transition to evade apoptosis and subsequently re-enter the cell cycle to regenerate damaged tissue. Entry into and exit from this arrest, known as “quiescence,” is governed by the inhibition of mTORC1. The pharmacological suppression of mTORC1 with rapamycin prevents quiescent stem cells from re-entering the cell cycle and impairs tissue regeneration. Rapamycin holds great therapeutic promise in preventing tumor regrowth from dormant cancer stem cells. Yet the extent to which genetic background impacts the known variation in the pharmacological response of rapamycin remains unknown. Here, we show that natural genetic variation across the Drosophila Genetics Reference Panel (DGRP) drives substantial differences in the rapamycin-mediated suppression of post-IR quiescence and regeneration. To define the basis of this differential sensitivity, we examined mitochondrial turnover and DNA damage repair—processes controlling IR-induced dormancy. Our analyses reveal that variation in rapamycin sensitivity is more strongly associated with differences in mitochondrial dynamics than with DNA damage response following radiation. Together, these findings demonstrate that genetic background is a critical determinant of rapamycin efficacy and identify mitochondrial regulation as a key mechanism underlying differential therapeutic response. Full article

Background: Triple-negative breast cancers (TNBCs) are among the most aggressive breast tumors, due not only to the absence of clinically functional biomarkers used in other molecular subtypes, but also their marked heterogeneity and pronounced migratory and invasive behavior. The search for new molecules of interest for risk prediction, diagnosis and therapy stems from the class of long non-coding RNAs (lncRNAs), which often display context-dependent (“dual”) functions and tissue specificity. Among them, lncRNA LINC01133 stands out for its dysregulation across cancer, although its molecular role in TNBC remains unclear. Methods: In the present study, we used the human TNBC cell line Hs578T to generate a cell panel comprising the parental line (Hs578T_wt), the control line (Hs578T_ctr), and the LINC01133 knockout line (Hs578T_ko). Subsequently, we performed bulk RNA-Seq to identify KO-associated Differentially Expressed Genes (DEGs) using ko_vs_ctr as the primary contrast. Functional interpretation was achieved by Over-Representation Analysis (ORA) using Gene Ontology. We then conducted a comparative patient-cohort analysis using TCGA-BRCA Basal-like/TNBC cases (TCGA/BRCA n = 1098; Basal-like/TNBC n = 199), classified with the AIMS algorithm, and evaluated concordance between KO-associated signatures and patient tumor expression patterns via trend-based analyses across the LINC01133 expression levels and associated genes. Results: A total of 265 KO-dominant DEGs were identified in Hs578T_ko, reflecting transcriptional changes consistent with tumor progression, with enrichment of pathways associated with LINC01133 knockout including cell adhesion, cell–cell interactions, epithelial–mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling. The main DEGs included ITIH5, GLUL, CACNB2, PDX1, ASPN, PTGER3, MFAP4, PI15, EPHB6, and CPA3 with additional candidates, such as KAZN and the lncRNA gene SSC4D, which have been implicated in migration/invasion, ECM remodeling, or signaling across multiple tumor contexts. Translational analyses in TCGA-BRCA basal-like tumors suggested a descriptive association in which lower LINC01133 levels were accompanied by shifts in the expression trends of genes linked to ECM/EMT programs and modulation of genes related to cell adhesion and protease inhibition. Conclusions: These results suggest a transcriptional model in which LINC01133 is associated with TNBC-related gene expression programs in a concentration-dependent manner, with loss of LINC01133 being associated with a transcriptomic shift toward pro-migratory/ECM remodeling signatures. While functional validation is required to establish causality, these data support LINC01133 as a molecule of interest in breast cancer research. Full article

Disulfiram (DSF) is a well-established inhibitor of aldehyde dehydrogenases (ALDHs) and an FDA-approved drug for chronic alcoholism. DSF has gained attention as a versatile scaffold for drug repurposing. Its metabolite, diethyldithiocarbamate (DDTC), mediates multiple biological effects via metal chelation and covalent modification of key cysteine residues. Beyond its established anticancer properties, DSF modulates cancer stem cells, reactive oxygen species, proteasome function, and drug-resistance pathways. It also shows promise in metabolic disorders, including type 2 diabetes and obesity, by targeting enzymes such as fructose-1,6-bisphosphatase and α-glucosidase, and influences energy expenditure and autophagy. DSF exhibits antimicrobial and antiparasitic activity, enhances antibiotic efficacy against multidrug-resistant bacteria, and demonstrates antischistosomal and anti-Trichomonas effects, while also providing radioprotective benefits. The clinical translation of DSF is limited by poor solubility, rapid metabolism, and off-target effects; consequently, the development of DSF analogs has become a major focus. Structural optimization has yielded derivatives with improved selectivity, stability, solubility, and target specificity, enabling precise modulation of key enzymes while reducing adverse effects. A key structure-based strategy involves introducing bulkier substituents to exploit differences in ALDH active-site architecture and achieve target selectivity. This concept is exemplified by compounds (1) and (2), in which bulky substituents confer selective inhibition of ALDH1A1 while sparing ALDH2. This review provides a comprehensive overview of DSF analogs, their molecular mechanisms, and therapeutic potential, highlighting their promise as multifunctional agents for cancer, metabolic disorders, infectious diseases, and radioprotection. Full article

Epithelial–mesenchymal plasticity encompasses a spectrum of epithelial and mesenchymal identity states that enable cells to adapt to changing biological contexts. While CD44 isoform usage and epithelial splicing regulators ESRP1/2 are well-characterized in cancer-associated epithelial–mesenchymal transition (EMT), their regulation across physiological, non-transformed identity states remains less well defined. Here, we employed a non-malignant human cellular system comprising primary dermal fibroblasts, induced pluripotent stem (iPS) cells, and iPS-derived mesenchymal stem cells (iPS-MSCs) to define discrete epithelial, intermediate epithelial/mesenchymal, and mesenchymal identity states positioned along an epithelial–mesenchymal identity axis. Morphological assessment, lineage marker profiling, and RT-qPCR analyses revealed reproducible population-level stratification of these states. CD44 expression and alternative splicing followed this hierarchy, with CD44s predominating in fibroblasts, broad variant exon inclusion in iPS cells, and intermediate patterns in iPS-MSCs. ESRP1 expression mirrored CD44 splicing architecture, and ESRP1 silencing in iPS cells induced a shift toward CD44s, confirming its functional contribution to epithelial-associated CD44 splicing. In contrast, Notch-related transcriptional readouts displayed distinct, context-dependent profiles across the examined identity states. Together, this study establishes a tractable non-transformed human model that captures selected molecular features associated with epithelial–mesenchymal plasticity beyond malignant contexts. Full article

The tumor microenvironment (TME), composed of various immune and non-immune cells, as well as cancer stem cells, plays a critical role not only in promoting cancer cell proliferation and metastasis but also in modulating therapeutic response. A wide range of therapeutic strategies targeting the TME are currently employed in cancer treatment, including standard chemotherapy, radiotherapy, immunotherapy, anti-angiogenic therapies, agents targeting cancer-associated fibroblasts (CAFs), oncolytic viruses (OVs), cold atmospheric plasma therapy, and nanovaccines. This review provides a comprehensive overview of the influence of the TME on cancer sensitivity to these therapies across all types of solid tumors. Full article

Cancer remains one of the most prominent global health concerns, posing a substantial threat to public health. Millions of people die from cancer each year, and many cancer types remain incurable at present. Conventional cancer treatments, including surgery, chemotherapy, radiotherapy, and immunotherapy, often fail to achieve optimal clinical outcomes and are frequently associated with severe trauma and adverse effects. Consequently, there is an urgent need to develop novel therapeutic strategies to address these limitations. Hydrogels have been widely utilised as platforms for loading drugs, proteins, DNA, and stem cells in biomedical tissue repair and cancer therapy. Through modification of their physicochemical properties and functions, hydrogels can be endowed with responsiveness to multiple stimuli. In recent years, stimuli-responsive hydrogels (also known as smart-responsive hydrogels), as novel drug delivery systems, have demonstrated remarkable efficacy in cancer treatment. Stimuli-responsive hydrogels are capable of altering their mechanical properties, swelling behaviour, hydrophilicity, bioactivity, and molecular permeability in response to endogenous stimuli (including pH, ROS, and temperature) and exogenous stimuli (including light, ultrasound, and magnetic fields). This review highlights recent advances and applications of responsive hydrogels triggered by endogenous stimuli (including pH, ROS, and temperature) and exogenous stimuli (including light, ultrasound, and magnetic force) in cancer drug delivery and treatment. Finally, the current application limitations and future prospects of smart-responsive hydrogels are summarised. Full article

The Maternal Embryonic Leucine Zipper Kinase (MELK) gene is a member of the Snf1/AMPK serine/threonine kinase family. MELK has recently attracted considerable interest in cancer biology due to its aberrant overexpression in various malignancies, including glioma, breast, lung, colorectal, gastric, and hematological cancers. It has been shown that higher MELK levels are often correlated with unfavorable prognosis, aggressive tumor manifestations, resistance to treatment, and stem-like tumor morphologies. In this review we aim to summarize the current understanding of MELK biology, including its functions in cell cycle regulation, apoptosis, oncogenic signaling pathways, and tumor stemness. We also discuss the therapeutic potential, limitations, and controversy of MELK inhibitors, and implications in cancer diagnosis and treatment. MELK may not be a universal driver oncogene; nonetheless, it is consistently linked to aggressive disease, underscoring its potential as a prognostic biomarker and a candidate for therapeutic co-targeting in combination treatments. Full article

Colorectal cancer (CRC) progression and therapy resistance are driven in part by metabolic reprogramming and the persistence of cancer stem-like cells (CSCs). The seven in absentia homolog 2 (SIAH2)/with-no-lysine kinase 1 (WNK1) signaling axis has emerged as a potential regulator of these processes, yet its functional role in CRC metabolism and tumor–stroma crosstalk remains incompletely understood. Integrated analyses of The Cancer Genome Atlas–Colon Adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus (GEO, GSE17538) datasets revealed significant upregulation of SIAH2 and WNK1 in CRC tissues, with strong positive correlations to glycolysis- and hypoxia-associated genes, including PFKP, LDHA, BPGM, ADH1A, ADH1B, and HIF-1α. Single-cell and clinical profiling further demonstrated preferential enrichment of SIAH2 in undifferentiated, stem-like tumor cell populations. Functional studies across multiple CRC cell lines showed that SIAH2 silencing suppressed proliferation, clonogenic growth, tumor sphere formation, and cell-cycle progression, whereas SIAH2 overexpression exerted opposite effects. Seahorse extracellular flux analyses established that SIAH2 promotes glycolytic capacity and metabolic flexibility. At the protein level, SIAH2 regulated glycolytic enzymes and WNK1/hypoxia-inducible factor-1α (HIF-1α) signaling, effects that were amplified by cancer-associated fibroblast (CAF)-derived conditioned medium. CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target. Full article

Organoid culture represents a sophisticated biological model that surpasses traditional two-dimensional (2D) methods and animal models in physiological relevance and cost-effectiveness. Current organoid systems derive from adult, fetal, and induced pluripotent stem cells, providing innovative platforms for studying organ development, disease pathogenesis, and drug discovery. Recent technological advances now enable respiratory organoids to significantly contribute to respiratory disease research. This review comprehensively synthesizes the development of respiratory organoid models and their applications in studying major respiratory diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and lung cancer. It further evaluates the transformative potential of these models in advancing respiratory disease research. Respiratory organoids uniquely model disease mechanisms and drug responses in human-specific microenvironments, enabling pathogenesis studies of respiratory diseases. They serve as functional platforms for drug screening and personalized therapy development. Future integration of multi-organoid systems with precision medicine promises to redefine respiratory disease research paradigms. Full article

Despite a thorough understanding of the structure of human papillomavirus (HPV) and its genotypic variations (high-risk and low-risk variants), the mechanisms underlying HPV-induced cervical cancer (CC) pathogenesis and the molecular signatures of drug resistance remain to be fully understood. Accumulating evidence has shown the involvement of kinase targets in the induction of drug resistance in high-risk (HR) HPV-CC. Molecularly, the genome of high-risk HPV is reported to control the expression of host kinases. In particular, Aurora kinases A, B, and C (ARKA, ARKB, and ARKC), phosphotidylinositol–trisphosphate kinase (PI3K)-Akt, and Glycogen synthase kinase3-α/β (GSK3 α/β) promote the transformation of infected cells, and also enhance the resistance of cells to various chemotherapeutic agents such as nelfinavir and cisplatin. However, the precise mechanisms through which HPV activates these kinases are yet to be fully elucidated. Furthermore, there is still ambiguity surrounding whether targeting HPV-induced kinases along with HPV-targeted therapies (such as phytopharmaceuticals and PROTAC/CRISPR-CAS-based systems) synergistically inhibit cervical tumor growth. Given the critical role of kinases in the pathogenesis and treatment of CC, a comprehensive review of current evidence is warranted. This review aims to provide key insights into the mechanisms of HPV-induced CC development, the involvement of kinases in drug resistance induction, and the rationale for combination therapies to improve clinical outcomes. Full article

Ovarian cancer is the deadliest gynecologic cancer, mainly because it is often diagnosed late and resists standard treatments. The tumor microenvironment (TME) plays a major role in disease progression and therapy failure. Two key components of the TME, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), create conditions that facilitate tumor growth and immune evasion. CAFs are highly diverse and originate from sources like fibroblasts and stem cells. They support cancer by remodeling the extracellular matrix, promoting angiogenesis, and releasing cytokines and growth factors that aid tumor survival. TAMs, which are usually in an M2 state, also promote metastasis and suppress immune responses by secreting immunosuppressive molecules. Together, CAFs and TAMs interact with cancer cells to activate pathways such as the TGF-β, IL-6, and PI3K/AKT pathways, which drive resistance to therapy. New treatments aim to block these interactions by targeting CAFs and TAMs through depletion, reprogramming, or pathway inhibition, often combined with immunotherapy. Advances such as single-cell sequencing and spatial transcriptomics now enable more precise identification of CAF and TAM subtypes, enabling more targeted therapies. This review summarizes their roles in epithelial ovarian cancer and explores how targeting these cells could improve outcomes. Full article

Cancer stem cells (CSCs) represent a small but highly resilient tumor subpopulation responsible for sustained growth, metastasis, therapeutic resistance, and recurrence. Their survival is supported by aberrant activation of developmental and inflammatory pathways, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt/mTOR, STAT3, and NF-κB, as well as epithelial–mesenchymal transition (EMT) programs and niche-driven cues. Increasing evidence shows that phytochemicals, naturally occurring bioactive compounds from medicinal plants, can disrupt these networks through multi-targeted mechanisms. This review synthesizes current findings on prominent phytochemicals such as curcumin, sulforaphane, resveratrol, EGCG, genistein, quercetin, parthenolide, berberine, and withaferin A. Collectively, these compounds suppress CSC self-renewal, reduce sphere-forming capacity, diminish ALDH⁺ and CD44⁺/CD24⁻ fractions, reverse EMT features, and interfere with key transcriptional regulators that maintain stemness. Many phytochemicals also sensitize CSCs to chemotherapeutic agents by downregulating drug-efflux transporters (e.g., ABCB1, ABCG2) and lowering survival thresholds, resulting in enhanced apoptosis and reduced tumor-initiating potential. This review further highlights the translational challenges associated with poor solubility, rapid metabolism, and limited bioavailability of free phytochemicals. Emerging nanotechnology-based delivery systems, including polymeric nanoparticles, lipid carriers, hybrid nanocapsules, and ligand-targeted formulations, show promise in improving stability, tumor accumulation, and CSC-specific targeting. These nanoformulations consistently enhance intracellular uptake and amplify anti-CSC effects in preclinical models. Overall, the consolidated evidence supports phytochemicals as potent modulators of CSC biology and underscores the need for optimized delivery strategies and evidence-based combination regimens to achieve meaningful clinical benefit. Full article

As a type of cell with self-renewal ability and multi-directional differentiation potential, stem cells are closely related to their functions, such as reprogramming transcription factors, histone modifications, and energy metabolism. m⁶A (N⁶-methyladenosine modification) is one of the most abundant modifications in RNA, and dynamic reversible m⁶A modification plays an important role in regulating stem cell function. This review moves beyond listing isolated functions and instead adopts an integrated perspective, viewing m⁶A as a temporal regulator of cellular state transitions. We discuss how m⁶A dynamically regulates stem cell pluripotency, coordinates epigenetic and metabolic reprogramming, and serves as a central hub integrating key signaling pathways (Wnt, PI3K-AKT, JAK-STAT, and Hippo). Finally, using somatic reprogramming as an example, we elucidate the stage-specific role of m⁶A in complex fate transitions. This comprehensive exposition not only clarifies the context-dependent logic of m⁶A regulation but also provides a precise framework for targeting the m⁶A axis in regenerative medicine and cancer therapy. Full article