Search Results (2,379)

Recent years have provided numerous reports on the mechanisms of action of psychiatric medications (antidepressants, antipsychotics, mood stabilizers, and antidementia drugs) that directly inhibit the growth of cancer cells, as well as on their indirect effects on the psyche and immune system, and their supportive effects on chemotherapeutic agents. The mechanisms of the anticancer activity of psychiatric drugs include inhibition of dopamine and N-methyl-D-aspartate receptors that work via signaling pathways (PI3K/AKT/mTOR/NF-κB, ERK, Wnt/ß-catenin, and bcl2), metabolic pathways (ornithine decarboxylase, intracellular cholesterol transport, lysosomal enzymes, and glycolysis), autophagy, Ca²⁺-dependent signaling cascades, and various other proteins (actin-related protein complex, sirtuin 1, p21, p53, etc.). The anticancer potential of psychiatric drugs seems to be extremely broad, and the most extensive anticancer literature has been reported on antidepressants (fluoxetine, amitriptyline, imipramine, mirtazapine, and St John’s Wort) and antipsychotics (chlorpromazine, pimozide, thioridazine, and trifluoperazine). Among mood stabilizers, lithium and valproates have the largest body of literature. Among antidementia drugs, memantine has documented anticancer effects, while there is limited evidence for galantamine. Of the new psychiatric substances, the antipsychotic drug brexpiprazole and the antidepressant vortioxetine have a very interesting body of literature regarding glioblastoma, based on in vitro and in vivo animal survival studies. Their use in brain tumors and metastases is particularly compelling, as these substances readily cross the blood–brain barrier (BBB). Moreover, the synergistic effect of psychiatric drugs with traditional cancer treatment seems to be extremely important in the fight against chemo- and radio-resistance of tumors. Although there are some studies describing the possible carcinogenic effects of psychiatric drugs in animals, the anticancer effect seems to be extremely significant, especially in combination treatment with radio/chemotherapy. The emerging evidence supporting the anticancer properties of psychiatric drugs presents an exciting frontier in oncology. The anticancer properties of psychiatric drugs may prove particularly useful in the period between chemotherapy and radiotherapy sessions to maintain the tumor-inhibitory effect. While further research is necessary to elucidate the mechanisms, clinical implications, dose-dependence of the effect, and clear guidelines for the use of psychiatric medications in cancer therapy, the potential for these commonly prescribed medications to contribute to cancer treatment enhances their value in the management of patients facing the dual challenges of mental health and cancer. Full article

Cancer is a leading cause of death worldwide, causing about 10 million deaths annually. Obesity contributes to cancer progression by inducing chronic inflammation, immunosuppressive microenvironment, metabolic dysfunction, and therapeutic resistance. Accumulating evidence shows that obesity can advance the infiltration of immunosuppressive cells and ameliorate the function and cytotoxicity of tumor-killing cells such as natural killer cells, natural killer T cells, macrophages, and CD8 T cells in cancer patients, resulting in cancer progression. Understanding the molecular signaling pathways involved in obesity-induced immunosuppression and cancer cell proliferation enables us to screen new biomarkers for cancer early diagnosis and improve anti-tumor therapeutic efficacy in obese patients with cancer. In this review, we first review the molecular mechanisms by which obesity induces the immunosuppressive landscape in the tumor microenvironment and some key obesity-associated factors causing immunotherapeutic suppression and metabolic dysfunction. Then, the application of natural products in the treatment of obesity and obesity-associated cancers is summarized. In addition, we discuss the contradictory functions of obesity in cancer risk and treatment outcome. The potent roles of precision medicine and artificial intelligence in the management of obesity-related cancers are highlighted. Full article

STK26 is highly expressed in colorectal cancer (CRC) and linked to tumorigenesis. Although implicated in unfolded protein response (UPR)-related oxidative stress, whether STK26 regulates CRC occurrence via the ATF6 pathway—a classic UPR branch governing proteostasis and cell survival—remains unestablished. In our research, we found that STK26 expression aberrantly upregulated in CRC is closely associated with poor prognosis. In vitro, tumor phenotype assays showed that STK26 drives CRC cell growth, proliferation, and migration. These effects were reversed by the ATF6 inhibitor Ceapin-A7, demonstrating that STK26’s oncogenic function depends on ATF6. Moreover, transcriptome sequencing revealed that STK26 is associated with the protein folding, sorting, and degradation pathway, and a luciferase reporter assay showed that STK26 activated the ATF6 signal pathway. Furthermore STK26 interacted with p50ATF6 and enhanced its protein stabilization. In vivo studies demonstrated that the administration of the STK26 inhibitor Hesperadin significantly suppressed CRC growth, suggesting a tumor-promoting role for STK26 in CRC pathogenesis. In summary, our research reveals that STK26 is a novel regulator that promotes the growth, proliferation, and migration of CRC cells by activating the ATF6 signaling pathway and stabilizing p50ATF6. Hence, the STK26-ATF6 axis has the potential to become a new target for treating colorectal cancer. Full article

The pregnane X receptor (PXR), a ligand-activated nuclear receptor, plays a central role in regulating the metabolism of both endogenous substances and xenobiotics. In recent years, increasing evidence has highlighted its involvement in chronic diseases, particularly metabolic disorders and cancer. PXR modulates drug-metabolizing enzymes, transporters, inflammatory factors, lipid metabolism, and immune-related pathways, contributing to the maintenance of hepatic–intestinal barrier homeostasis, energy metabolism, and inflammatory responses. Specifically, in type 2 diabetes mellitus (T2DM), PXR influences disease progression by regulating glucose metabolism and insulin sensitivity. In obesity, it affects adipogenesis and inflammatory processes. In atherosclerosis (AS), PXR exerts protective effects through cholesterol metabolism and anti-inflammatory actions. In metabolic dysfunction-associated steatotic liver disease (MASLD), it is closely associated with lipid synthesis, oxidative stress, and gut microbiota balance. Moreover, PXR plays dual roles in various cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer. Currently, PXR-targeted strategies, such as small molecule agonists and antagonists, represent promising therapeutic avenues for treating metabolic diseases and cancer. This review comprehensively summarizes the structural features, signaling pathways, and gene regulatory functions of PXR, as well as its role in metabolic diseases and cancer, providing insights into its therapeutic potential and future drug development challenges. Full article

Background: Pancreatic cancer ranks as the fourth leading cause of cancer-related deaths in the USA. The human aldehyde dehydrogenase (ALDH) family comprises 19 functional members and has been implicated in prognosis and therapy resistance. However, it remains unclear which specific ALDHs are associated with adverse prognoses in pancreatic cancer. Methods: We obtained transcriptomic and clinical data for pancreatic adenocarcinoma (PAAD) from the TCGA, corresponding mutational data, and normal pancreatic tissue transcriptomic data from GTEx. Prognostic analysis was carried out using Kaplan–Meier analysis. KEGG and GO analyses were used for biological signaling pathways, and ESTIMATE algorithms were used for tumor microenvironment (TME) assessment. CIBERSORT algorithm, immune infiltration analysis, and OncoPredict algorithms were employed for predicting chemotherapy sensitivity. Results: Our study identified four of the 19 ALDH genes (ALDH1L1, ALDH3A1, ALDH3B1, ALDH5A1) that were significantly associated with pancreatic cancer prognosis. High expression of ALDH1L1, ALDH3A1, and ALDH3B1 was associated with shorter overall survival, while ALDH5A1 expression was associated with longer overall survival of pancreatic cancer patients. Clinicopathological analysis revealed a significant association with KRAS mutational status and ALDH3A1 expression. Immune correlation analysis indicated that high expression of ALDH3A1 and ALDH3B1 was associated with lower expression of CD8⁺ T cell-associated gene expression. ESTIMATE analyses further revealed that high expression of ALDH3A1 and ALDH3B1 was associated with lower levels of immune cell infiltration. PAAD tumors with low ALDH3A1 expression were more sensitive to paclitaxel. Immunohistochemical analysis demonstrated high expression of ALDH3A1 in pancreatic cancer cells of human tumor tissues compared to normal pancreatic tissues. Conclusions: This study unveils specific ALDH family members relevant for prognosis and chemotherapy response in pancreatic cancer patients. These findings contribute valuable insights into prognostic biomarkers and their potential clinical utility in the treatment of pancreatic adenocarcinoma. Full article

Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide, with aberrant activation of the Wnt/β-catenin signaling pathway constituting a key driver of tumorigenesis. SALL2, a zinc finger transcription factor deregulated in various cancers, has been implicated in Wnt signaling regulation through its Xenopus ortholog; however, its role in human CRC remains unclear. In this study, we investigated the expression and function of SALL2 in CRC. Immunohistochemical analysis revealed that SALL2 is present in the epithelium and stroma of normal colon tissue but is significantly downregulated in adenomas, carcinomas, and CRC cell lines. Reduced SALL2 expression was associated with elevated levels of active β-catenin and poorer overall patient survival. Functional assays demonstrated that SALL2 transcriptionally activates AXIN2, a key negative regulator of the Wnt/β-catenin pathway. Chromatin immunoprecipitation and promoter-reporter assays confirmed SALL2 binding to the AXIN2 proximal promoter and enhanced promoter activity. Furthermore, SALL2 expression potentiated the pro-apoptotic effects of the Wnt pathway inhibitor XAV939 in CRC cells, suggesting a role in sensitizing cells to Wnt-targeted therapies. Collectively, these findings identify SALL2 as a negative regulator of Wnt/β-catenin signaling and support its potential as a prognostic biomarker and therapeutic target in colorectal cancer. Full article

Background: Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide. Its high recurrence rate and limited treatment options underscore the urgent need for the development of new and highly effective drugs. Methods: This study systematically explores the molecular mechanism of cinnamic acid against hepatocellular carcinoma through integrated machine learning prediction, network pharmacological analysis and in vitro experimental verification. Results: The prediction of anti-tumor activity based on the random forest model showed that cinnamic acid has significant anti-tumor potential (probability = 0.69). Network pharmacology screened 185 intersection targets of cinnamic acid and liver cancer, of which 39 core targets (such as PIK3R1, AKT1, MAPK1) were identified as key regulatory hubs through protein interaction network and topological analysis. Functional enrichment analysis showed that these targets were mainly enriched in the PI3K/AKT signaling pathway (p = 2.1 × 10⁻¹²), the cancer pathway (p = 3.8 × 10⁻¹⁰), and apoptosis-related biological processes. Molecular docking validation revealed that the binding energies of cinnamic acid with the 19 core targets were all below −5 kcal/mol, a threshold indicating strong binding affinity in molecular docking. The binding modes to PIK3R1 (−5.4 kcal/mol) and AKT1 (−5.1 kcal/mol) stabilized through hydrogen bonding. In vitro, cinnamic acid dose-dependently inhibited Hep3B proliferation/migration, induced apoptosis, downregulated PI3K, p-AKT, and Bcl-2, and upregulated Bax and Caspase-3/8. Conclusions: This study systematically reveals, for the first time, that the multi-target mechanism of cinnamic acid exerts anti-hepatic cancer effects by targeting the PI3K/AKT signaling pathway, supporting its potential as a natural anti-tumor drug. Full article

Tumor-initiating cells (TICs) constitute a subpopulation of cancer cells with stem-like properties contributing to tumorigenesis, progression, recurrence, and therapeutic resistance. Despite their biological importance, their molecular signatures that distinguish them from non-TICs remain incompletely characterized. This study aimed to comprehensively analyze transcriptomic differences between TICs and non-TICs, identify TIC-specific gene expression patterns, and construct a machine learning-based classifier that could accurately predict TIC status. RNA sequencing data were obtained from four human cell lines representing TIC (TS10 and TS32) and non-TIC (32A and Epi). Transcriptomic profiles were analyzed via principal component, hierarchical clustering, and differential expression analysis. Gene-Ontology and Kyoto-Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted for functional interpretation. A logistic-regression model was trained on differentially expressed genes to predict TIC status. Model performance was validated using synthetic data and external projection. TICs exhibited distinct transcriptomic signatures, including enrichment of non-coding RNAs (e.g., MIR4737 and SNORD19) and selective upregulation of metabolic transporters (e.g., SLC25A1, SLC16A1, and FASN). Functional pathway analysis revealed TIC-specific activation of oxidative phosphorylation, PI3K-Akt signaling, and ribosome-related processes. The logistic-regression model achieved perfect classification (area under the curve of 1.00), and its key features indicated metabolic and translational reprogramming unique to TICs. Transcriptomic state-space embedding analysis suggested reversible transitions between TIC and non-TIC states driven by transcriptional and epigenetic regulators. This study reveals a unique transcriptomic landscape defining TICs and establishes a highly accurate machine learning-based TIC classifier. These findings enhance our understanding of TIC biology and show promising strategies for TIC-targeted diagnostics and therapeutic interventions. Full article

Ferroptosis is an iron-dependent form of regulated cell death marked by lipid peroxidation in polyunsaturated phospholipids. In head and neck cancer (HNC), where resistance to chemotherapy and immunotherapy is common, ferroptosis offers a mechanistically distinct strategy to overcome therapeutic failure. However, cancer cells often evade ferroptosis via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and iron-regulatory genes. HNC remains therapeutically challenging due to therapy resistance driven by redox adaptation. This review highlights the ferroptosis pathway—a form of regulated necrosis driven by iron and lipid peroxidation—and its regulation by Nrf2, a master antioxidant transcription factor. We detail how Nrf2 contributes to ferroptosis evasion in HNC and summarize emerging preclinical studies targeting this axis. The review aims to synthesize molecular insights and propose therapeutic perspectives for overcoming resistance in HNC by modulating Nrf2–ferroptosis signaling. We conducted a structured narrative review of the literature using PubMed databases. Relevant studies from 2015 to 2025 focusing on ferroptosis, Nrf2 signaling, and head and neck cancer were selected based on their experimental design, novelty, and relevance to clinical resistance mechanisms. In HNC, Nrf2 mediates resistance through transcriptional upregulation of GPX4 and SLC7A11, epigenetic stabilization by PRMT4 and ALKBH5, and activation by FGF5 and platelet-derived extracellular vesicles. Epstein–Barr virus (EBV) infection also enhances Nrf2 signaling in nasopharyngeal carcinoma. More recently, loss-of-function KEAP1 mutations have been linked to persistent Nrf2 activation and upregulation of NQO1, which confer resistance to both ferroptosis and immune checkpoint therapy. Targeting NQO1 in KEAP1-deficient models restores ferroptosis and reactivates antitumor immunity. Additionally, the natural alkaloid trigonelline has shown promise in reversing Nrf2-mediated ferroptosis resistance in cisplatin-refractory tumors. Pharmacologic agents such as auranofin, fucoxanthin, carnosic acid, and disulfiram/copper complexes have demonstrated efficacy in sensitizing HNC to ferroptosis by disrupting the Nrf2 axis. This review summarizes emerging mechanisms of ferroptosis evasion and highlights therapeutic strategies targeting the Nrf2–ferroptosis network. Integrating ferroptosis inducers with immune and chemotherapeutic approaches may provide new opportunities for overcoming resistance in head and neck malignancies. Full article

The serine protease kazal-type inhibitor (SPINK) family is central to the regulation of proteolytic function, the establishment of physiological homeostasis, and the development of many disease states, including cancer. Emerging research has identified that members of the SPINK family are commonly overexpressed in most malignancies and are deeply implicated in pivotal oncogenic pathways like cell growth, epithelial-to-mesenchymal transition (EMT), metastasis, and drug resistance. This review provides an in-depth examination of structural and functional characteristics of SPINK proteins and their involvement in the onset and development of multiple cancers, which include prostrate, pancreatic, and colorectal carcinomas. Significantly, SPINK proteins regulate major signalling pathways, including EGFR, NF-κB, and MAPK, highlighting their role as prognostic biomarkers and therapeutic targets. The review underscores the most recent advancements in therapeutic strategies for SPINK-related pathways and outlines the bottlenecks that have restricted their use in the clinic. By integrating current evidence, this work signals the potential of SPINK proteins as good precision oncology candidates with novel options for cancer prognosis, treatment, and management. Full article

Background/Objectives: Colorectal cancer (CRC) is one of the most common malignancies worldwide. microRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression post-transcriptionally and have emerged as important regulators in cancer biology. This study aimed to investigate the roles of miR-379-5p and miR-519a-3p in CRC using Quantitative Real-Time PCR (RT-qPCR) and comprehensive bioinformatic analyses. Methods: Tumor tissues and matched adjacent normal tissues were collected from 54 patients with CRC. The expression levels of miR-379-5p and miR-519a-3p in these tissues were determined using the RT-qPCR method. To investigate the functional roles of differently expressed miRNAs, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to construct miRNA–transcription factor (TF)–target gene–disease interaction networks. Results: It was found that the expression level of miR-379-5p was statistically significantly increased in tumor tissues compared to normal tissues, while miR-519a-3p was decreased (p < 0.05). GO analysis revealed enrichment in several important biological processes, including cellular protein metabolic processes, biosynthetic processes, response to stress, and nucleic acid binding TF activity. KEGG analysis exhibited that dysregulated miRNAs were associated with important pathways related to carcinogenesis, such as p53 signaling, TGF-beta signaling, and FoxO signaling pathways. Additionally, the miRNAs-TFs-Genes-Diseases Networks analysis identified ESR1 and FOXA1 as common target TFs of dysregulated miRNAs. Network analyses showed that dysregulated miRNAs interact with CRC-associated genes (Caspase 3 (CASP3), Adenomatous polyposis coli (APC), and AKT serine/threonine kinase 3 (AKT3)). Conclusions: The present study indicates that miR-379-5p and miR-519a-3p may be involved in CRC progression, with miR-379-5p being upregulated and miR-519a-3p being downregulated in tumor tissues. However, further functional studies are required to clarify their potential roles in tumor biology. The findings of the study suggest that miR-379-5p and miR-519a-3p may be associated with regulatory pathways related to CRC. These miRNAs have the potential to serve as diagnostic biomarkers or therapeutic targets in CRC. Full article

Cellular senescence, a state of permanent cell cycle arrest, represents a double-edged sword in biology—providing tumor-suppressive functions while contributing to tissue degeneration, chronic inflammation, and age-related diseases when senescent cells persist. A key driver of senescence is oxidative stress, primarily mediated by excessive reactive oxygen species that damage mitochondrial DNA, modulate redox-sensitive signaling pathways, and trigger the senescence-associated secretory phenotype. Emerging evidence highlights the pathogenic role of SASP in promoting local inflammation, immune evasion, and senescence propagation. This review explores the intricate interplay between redox imbalance and cellular senescence, emphasizing mitochondrial dysfunction, SASP dynamics, and their implications in aging and cancer. We discuss current senotherapeutic strategies—including senolytics, senomorphics, antioxidants, gene therapy, and immunotherapy—that aim to eliminate or modulate senescent cells to restore tissue homeostasis. Understanding the heterogeneity and context-specific behavior of senescent cells remains crucial for optimizing these therapies. Future research should focus on addressing key knowledge gaps, including the standardization of senescence biomarkers such as circulating miRNAs, refinement of predictive preclinical models, and development of composite clinical endpoints. These efforts are essential to translate mechanistic insights into effective senotherapeutic interventions and enable the safe integration of senescence-targeting strategies into routine clinical practice. Full article

Background: Bladder cancer is a common and heterogeneous malignancy of the urinary tract. Traditional chemotherapy using bivalent platinum drugs such as cisplatin(CDDP) is often limited by severe side effects and acquired resistance. To overcome these limitations, we explored a novel Pt(IV) prodrug, DNP, designed to release both cytotoxic cisplatin and the anti-inflammatory cyclooxygenase-2 (COX-2) inhibitor naproxen(NPX). Methods: We evaluated the cytotoxic activity of DNP using both two-dimensional (2D) monolayer and three-dimensional (3D) spheroid models of bladder cancer cells. Transcriptomic analysis via RNA-seq identified apoptosis- and inflammation-related signaling pathways modulated by DNP. RNA-seq-based transcriptomic profiling revealed that DNP regulates signaling pathways associated with apoptosis and inflammation. The anti-inflammatory effects were evaluated using a lipopolysaccharide (LPS)-induced macrophage model, while the in vivo antitumor efficacy was assessed in an orthotopic MB49 bladder cancer model. Results: Compared with CDDP, DNP significantly increased intracellular platinum accumulation and exhibited superior cytotoxicity. It effectively inhibited tumor proliferation, induced apoptosis, and attenuated inflammation both in vitro and in vivo. Conclusions: These findings suggest that DNP exerts dual antitumor effects through enhanced delivery of cytotoxic and anti-inflammatory agents, offering a promising strategy for bladder cancer therapy. Full article

Melanoma is one of the most invasive skin cancers with the highest mortality risk. The PI3K/AKT/mTOR signaling pathways are a key regulatory point related to growth factors and involved in the cell’s energy metabolism. They are responsible for cell life processes such as growth, proliferation, invasion, survival, apoptosis, autophagy, and angiogenesis. The studies undertaken concerned the effect of protein kinase inhibitors involved in the signaling pathways of AKT, MEK, and mTOR kinases on the expression of cytoskeletal and extracellular matrix proteins, invasion process, and activities of the matrix metalloproteinases (MMPs): MMP-2 and MMP-9 in melanoma cells. The study used mTOR kinase inhibitors: Everolimus and Torkinib; dual PI3K/mTOR inhibitors BEZ-235 and Omipalisib; and the mTORC1/2 inhibitor OSI-027. These compounds were used both as monotherapy and in combination with the MEK1/2 inhibitor AS-703026. mTOR kinase inhibitors, especially the third generation in combination with the MEK 1/2 kinase inhibitor AS-703026, significantly inhibited invasion and metalloproteinases (MMPs) activity in melanoma cell lines. The inhibition of the cell invasion process was accompanied by a significant change in the expression of proteins associated with EMT. The morphology of cells also changed significantly: their thickness, volume, roughness, convexity of shape, and irregularity, which may be a good diagnostic and prognostic factor for the response to treatment. Our studies to date on the effect of three generations of mTOR kinase inhibitors on the inhibition of the invasion process, the activation of apoptosis, and the reduction in cell proliferation suggest that they may be an important target for anticancer therapy. Full article

Background: Breast cancer, one of the most researched cancers in oncology, remains the primary cause of cancer-related mortality in women. Its biological complexity, which includes phenotypic, genetic, and microenvironmental aspects, makes modeling and treatment quite difficult. The need for more physiologically realistic models is highlighted by the comparison of two-dimensional (2D) cell cultures with 3D breast-cancer-derived spheroids, which discloses how important pathways such as epidermal growth factor receptor (EGFR) and insulin-like growth factor I receptor (IGF-IR) influence cell behavior and extracellular matrix (ECM) macromolecular expression. Methods: The purpose of this study was to utilize novel 3D cell platforms to assess the effect of inhibiting the EGFR and IGF-IR pathways, alone or in combination, on the functional properties and the expression levels of certain matrix metalloproteinases (MMPs) which are implicated in breast cancer progression (i.e., triple-negative and luminal A breast cancer subtypes) and related with the EGFR and IGF-ΙR molecular network, as also demonstrated through STRING analysis. Results: Our results demonstrated potential crosstalk between EGFR and IGF-IR signaling, which influences cell proliferation and spheroid growth, dissemination, and migration. Significant phenotypic changes proposed between 2D and 3D cell cultures, and alterations in the expression of MMPs, were also recorded. Conclusions: Both breast cancer cell lines retained acknowledged characteristics across the tested models while also exhibiting new, condition-dependent properties. Overall, our findings enhance our understanding on the interplay between the EGFR and IGF-IR pathways and underscore the value of 3D models in revealing key biological processes underlying distinct breast cancer phenotypes. Full article