Antiproliferative effects of glucosamine, a glucose derivative with a similar structure to glucose, have been discovered, but the molecular mechanisms are not yet fully understood. Since glucosamine and glucose not only have similar structures but also are catalyzed by the same enzyme, hexokinase (HK), the present study delved into determining whether the antiproliferative effect of glucosamine involved the inhibition of glycolysis by competition with glucose. Whole‑genome screening analysis showed that a number of the gene pathways controlled by glucosamine were directly and indirectly involved in glycolysis. In vitro experiments revealed that as more glucose was added, the antiproliferative effect of glucosamine decreased. Also, it was found that glucosamine was transported into cells mainly through glucose transporter (GLUT) 2 which was responsible for the antiproliferative effects of glucosamine. In addition, the present study found that cancer cell lines with low expression level of HKII show high sensitivity to glucosamine and a HK inhibitor, 3‑bromopyruvate, enhanced the antiproliferative effect of glucosamine. Under hypoxic conditions, activated hypoxia‑inducible factor 1α (HIF‑1α) inducing glucose uptake and glycolysis hampered glucosamine‑induced cell death and HIF1A knockdown or HK inhibitors restored the antiproliferative effects of glucosamine. These findings demonstrated that glucosamine is an efficient glycolysis inhibitor and that GLUT2 and HKII play important roles as biomarkers for determining sensitivity to glucosamine. Moreover, the results suggested that the antiproliferative effect of glucosamine may be more efficient when administered in combination with other glycolytic agents or inhibitors targeting HIF‑1α.

Acute leukemia, a highly perilous cancer, is diagnosed using invasive procedures like bone marrow aspirate and biopsy (BMA/BMB). This study investigated the use of artificial intelligence (AI)-enhanced Fourier transform infrared (FT-IR) spectroscopy as a non-invasive, reagent-free diagnostic alternative with high sensitivity and specificity. The spectral peak patterns of peripheral blood smears (PBS) from clinically healthy individuals (n = 50) BMA/BMB-confirmed acute leukemia patients (n = 50) were examined in the 1800-850 cm-1 range. Six trained models were used to assess the diagnostic performance, focusing on accuracy, positive predictive value (PPV), negative predictive value (NPV), F1 score, and area under the receiver operating characteristic (ROC) curve (AUC). The study shows significantly lower absorbance peaks in leukemia cases compared to healthy controls across various spectral regions: 1637.82, 1528.63, 1448.29, and 1388.54 cm-1, 1302.02, and 1240.21 cm-1, and 1163.99 cm-1. These differences indicate decreased concentrations or distinct molecular configurations of proteins, lipids, nucleic acids, and carbohydrates in cases. Conversely, they exhibited elevated absorbance peaks at 1032.14 and 894.11 cm-1 regions, suggesting potential disparities in amino acid, DNA, fatty acid, and saccharide residues compared to healthy controls. Of the six trained models, the SVM model demonstrated remarkable diagnostic performance, achieving an accuracy of 83%, a PPV of 80%, an NPV of 86%, an F1 score of 82.47%, and an AUC of 90.76%. This study demonstrates the potential of AI-enhanced FT-IR spectroscopy as a valuable adjunct diagnostic tool for acute leukemia. By offering a less invasive and faster alternative to BMA/BMB, this approach can potentially enhance leukemia diagnosis and improve patient outcomes, particularly in pediatric and geriatric cases.

Bladder cancer (BCa), a prevalent malignancy of the urinary tract, is associated with high recurrence and mortality rates. SLC16A7, a member of the solute carrier family 16 (SLC16), encodes monocarboxylate transporters that are involved in the proton-coupled transport of metabolites, including lactate, pyruvate, and ketone bodies, across cell membranes. Evidence suggests that SLC16A7 exhibits variable expression in cancers and may influence tumor development, progression, and immune regulation. This study examined the role of SLC16A7 in cancer prognosis, progression, and immune regulation, focusing on BCa.

A comprehensive analysis was conducted to evaluate the clinical and immunological relevance of SLC16A7 across multiple cancer types using data from 33 tumor datasets from 'The Cancer Genome Atlas (TCGA). ' Associations between SLC16A7 expression and clinicopathological features, prognostic indicators, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and immune-related gene expression were systematically analyzed. Experimental validation was performed to assess SLC16A7 expression in the BCa tissues and cell lines. The prognostic value of SLC16A7 was confirmed using clinical follow-up data from an independent patient cohort. Functional studies included proliferation assays to investigate the effect of SLC16A7. CD8 + T cells were obtained from the peripheral blood of healthy donors and stimulated using CD3 and CD28 antibodies in combination with recombinant IL-2. To investigate the immunological role of SLC16A7, co-culture experiments were performed between BCa cells and activated CD8 + T cells. Additionally, CD8 + T cell chemotaxis assays and ELISA analyses were conducted to evaluate the immune responses mediated by SLC16A7.

SLC16A7 expression was downregulated in 16 cancer types, including BCa, and upregulated in three cancer types. Its expression was significantly associated with tumor stage in four cancers and showed both positive and negative correlations with prognosis, depending on the cancer type. Genomic analyses revealed significant associations between SLC16A7 and TMB in 13 cancer types and MSI in 11 cancer types. Pathway enrichment analyses (Hallmark-GSEA and KEGG-GSEA) indicated strong associations between SLC16A7, immune responses, and tumor progression. Immune infiltration analysis showed a predominantly positive association between SLC16A7 expression and immune cell infiltration, except in low-grade gliomas (LGG). CIBERSORT analysis demonstrated that SLC16A7 expression correlated positively with resting memory CD4 T cells, eosinophils, monocytes, resting mast cells, and memory B cells and negatively with activated memory CD4 T cells, M1 macrophages, follicular helper T cells, M0 macrophages, and CD8 T cells. SLC16A7 expression was also significantly associated with the expression of immune-regulatory molecules. Experimental validation showed reduced SLC16A7 expression in BCa tissues and cell lines compared to that in their normal counterparts. Kaplan-Meier survival analysis indicated that higher SLC16A7 expression was correlated with better overall survival in patients with BCa. Functional assays revealed that SLC16A7 inhibited BCa cell progression and promoted the chemotaxis and tumor-killing ability of CD8 + T cells in the BCa tumor microenvironment (TME).

SLC16A7 exhibits tumor-suppressive properties, with downregulation in most cancers, and is associated with favorable prognosis and enhanced immune responses. SLC16A7 functions as a tumor suppressor in BCa and is associated with improved survival outcomes. These findings suggest that SLC16A7 is a potential biomarker for cancer diagnosis and prognosis.

Urinary extracellular vesicles (uEVs), directly secreted from bladder cancer (BCa) cells, harbor potential for biomarker discovery.

We performed proteomic analysis to explore and validate uEV-based diagnostic markers for BCa, with a focus on cytoplasmic EV proteins. Among the 1960 proteins identified by shotgun proteomics (tandem mass tag-labeled liquid chromatography-tandem mass spectrometry [LC-MS/MS]) of uEVs from seven patients with BCa and four healthy individuals, 17 cytoplasmic EV proteins were significantly elevated in the patients' urine (fold change > 1.5; p < 0.05). These 17 proteins were subsequently validated using targeted proteomics (selected reaction monitoring/multiple reaction monitoring) using urine samples from 49 and 48 patients with and without BCa, respectively, including those with non-BCa hematuria.

Ten measurable EV proteins remained significantly elevated in the urine of patients with BCa, with EV-EIF2S1 demonstrating the best diagnostic performance (area under the receiver operating characteristic [ROC] curve [AUC] [ROCAUC]: 0.83). Additionally, EV-EIF2S1 distinguished patients with BCa from those without BCa and hematuria in a suitable manner (ROCAUC: 0.92). Functional analysis of EIF2S1 in the BCa cell lines (T24 and 5637) showed that EIF2S1 knockdown markedly inhibited cell proliferation and induced cell cycle arrest and apoptosis, suggesting its essentiality for BCa cell growth and survival.

This study identified EV-EIF2S1 as a novel, uEV-based BCa diagnostic marker and demonstrated its functional significance in BCa cell growth and survival.

Breast cancer is a leading cause of cancer-related deaths among women worldwide. The presence and function of CD8 + T cells in the tumor microenvironment have been associated with better patient outcomes. Drug toxicity has posed a significant challenge to the clinical implementation of chemotherapy-based strategies in cancer treatment.

In this study, we employed flow cytometry to investigate the potential synergistic immunomodulatory effects on CD8 + T cells in a mouse model of breast cancer by combining metformin, an anti-diabetic medication, with doxorubicin.

Through flow cytometry analysis, we observed that the combination of the two drugs led to an increased percentage of CD8 + T cells compared to either drug alone. The modulation of HIF-1α and  STAT3 gene expression in the combination group further confirmed the efficacy of this approach.

Our findings suggest that combining metformin with doxorubicin can enhance the anticancer activity of doxorubicin and decrease its cytotoxicity in a 4T1 breast cancer mouse model.

Initially identified as a regulator of complement activation on host cells, the known roles of CD46 (membrane cofactor protein [MCP]) have expanded. We now know that this ancient molecule is expressed on almost all nucleated cells as a family of four predominant isoforms. It also is involved in human reproduction, modulation of T cell activation and immunoinflammatory effector functions, autophagy, and the newly identified intracellular complement system (complosome). CD46 is also known as a "pathogen" magnet, being a port of entry for at least seven bacteria and five viruses. Moreover, CD46 has recently emerged as a key player in cancer biology. Numerous studies provide evidence of the association among elevated CD46 expression, malignant transformation, and metastasizing potential. These features, along with its roles as pathogen receptor, have made CD46 a target for cancer therapeutics. Thus, modified viral vectors (such as strains of adenovirus and measles virus) targeting CD46 currently are being exploited against a wide range of cancers. Another oncologic treatment utilizes a CD46-targeting human mAb as an antibody-drug conjugate. Herein, we review CD46 and its "multiverse" of cancer interactions.

Colorectal cancer (CRC) is a significant global health issue, with early detection being critical to improving patient survival. Dysregulation of the glycolysis pathway plays a pivotal role in CRC progression, but specific gene-level mechanisms remain underexplored.

This study aimed to investigate the role of glycolysis-related genes in CRC development and identify potential diagnostic and prognostic biomarkers.

We utilized The Cancer Genome Atlas (TCGA) dataset to perform differential expression analysis of glycolysis-related genes in CRC. Protein-protein interaction (PPI) network analysis was conducted to identify central hub genes. The diagnostic potential of selected genes was evaluated using ROC curve analysis, while their expression levels were validated through RT-qPCR.

IER3 and AGRN were identified as significantly upregulated genes associated with reduced survival rates in CRC patients. PPI analysis revealed their roles as central hub genes within the glycolysis pathway. ROC curve analysis demonstrated their ability to distinguish CRC patients from healthy individuals. Validation through RT-qPCR confirmed their significant overexpression in CRC samples, highlighting their involvement in disease progression.

IER3 and AGRN are critical components of the glycolysis pathway, driving CRC development and progression while also showing potential as biomarkers for predicting outcomes, diagnosing CRC, and serving as treatment targets.

Papillary thyroid cancer (PTC) is the most prevalent follicular cell-derived subtype of thyroid cancer. A systems biology approach to PTC can elucidate the mechanism by which molecular components work and interact with one another to decipher a panoramic view of the pathophysiology.

PTC associated genes and transcriptomic data were retrieved from DisGeNET and Gene Expression Omnibus database respectively. Published proteomic and metabolomic datasets in PTC from EMBL-EBI were used. Gene Ontology and pathway analyses were performed with SNPs, differentially expressed genes (DEGs), proteins, and metabolites linked to PTC. The effect of a nucleotide substitution on a protein's function was investigated. Additionally, significant transcription factors (TFs) and kinases were identified. An integrated strategy was used to analyse the multi-omics data to determine the key deregulated pathways in PTC carcinogenesis.

Pathways linked to carbohydrate, protein, and lipid metabolism, along with the immune response, signaling, apoptosis, gene expression, epithelial-mesenchymal transition (EMT), and disease onset, were identified as significant for the clinical and functional aspects of PTC. Glyoxylate and dicarboxylate metabolism and citrate cycle were the most common pathways among the PTC omics datasets. Commonality analysis deciphered five TFs and fifty-seven kinases crucial for PTC genesis and progression. Core deregulated pathways, TFs, and kinases modulate critical biological processes like proliferation, angiogenesis, immune infiltration, invasion, autophagy, EMT, and metastasis in PTC.

Identified dysregulated pathways, TFs and kinases are critical in PTC and may help in systems level understanding and device specific experiments, biomarkers, and drug targets for better management of PTC.

Resistance to drugs is one of the major issues affecting the response to pharmacological treatments for tumors. Different mechanisms have been proposed to explain the development of cancer drug resistance (CDR), and several approaches to overcome it have been suggested. However, the biological basis of CDR remains unclear. Here, we investigated whether mitochondrial damage and consequent mitochondrial dysfunction are major causes of drug resistance in different tumors. To this end, we used cell lines from three tumors: hepatocellular carcinoma, breast cancer, and colon cancer. We then applied a protocol that recapitulates chemotherapy regimens in patients, rendering each cell line resistant to the drug commonly used in their respective treatments. The combination of cellular respiration analysis, gene expression analysis of cytochrome c oxidase isoforms, and mass spectrometry assessment of cardiolipin (CL) reveals that mitochondrial dysfunction is the underlying cause of the resistant phenotype. Importantly, we disclosed for the first time the rapid inhibition of oxidative phosphorylation (OXPHOS) by l-lactate, the major product of fermentation. Finally, we demonstrated that inhibition of lactic acid fermentation and activation of OXPHOS can increase drug sensitivity in all tested drug-resistant cancer cells. Taken together, our results suggest that inhibiting fermentation and enhancing mitochondrial function in cancer cells may be a concrete option to control the worrisome phenomenon of CDR.NEW & NOTEWORTHY Cancer drug resistance (CDR) is increasingly becoming a concerning clinical problem. The mechanisms behind the onset of CDR are still not well defined. In this study, we demonstrated that a treatment mimicking long-term clinical protocols with commonly used chemotherapeutic agents promotes mitochondrial bioenergetic dysfunction, leading to the acquisition of CDR. In a future perspective, interventions aimed at inhibiting fermentation and restoring OXPHOS efficiency may offer tangible opportunities to reduce the clinical burden of CDR.

Colorectal cancer (CRC) affects the population worldwide, occupying the first place in terms of death and incidence. Synthetic peptides (SPs) emerged as alternative molecules due to their activity and low toxicity. Proteomic analysis of PepGAT-treated HCT-116 cells revealed a decreased abundance of proteins involved in ROS metabolism and energetic metabolisms, cell cycle, DNA repair, migration, invasion, cancer aggressiveness, and proteins involved in resistance to 5-FU. PepGAT induced earlier ROS and apoptosis in HCT-116 cells, cell cycle arrest, and inhibited HCT-116 migration. PepGAT enhances the action of 5-FU against HCT-116 cells by dropping down 6-fold the 5-FU toward HCT-116 and reduces its toxicity for non-cancerous cells. These findings strongly suggest the multiple mechanisms of action displayed by PepGAT against CRC cells and its potential to either be studied alone or in combination with 5-FU to develop new studies against CRC and might develop new drugs against it.

Hepatocellular carcinoma (HCC) is a malignant tumour with high prevalence and mortality rate worldwide. Metabolic reprogramming of cancer cells may be a major factor in the process of this disease. Glucose transporter proteins (GLUTs) are members of the major facilitator superfamily of membrane transporters, playing a pivotal role in the metabolic reprogramming and tumour progression in HCC. This review discusses the advances in the study of GLUTs in HCC, including the expression patterns, functions and possibilities of GLUTs. In HCC, the expression levels of GLUTs are closely associated with tumour aggressiveness, metabolic reprogramming and prognosis. A series of inhibitors have been demonstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models. These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells, thereby impeding tumour growth, and concurrently enhancing the sensitivity to chemotherapeutic agents. This reminds us of the urgent need to elucidate GLUTs' roles in HCC and to determine the most effective ways to translate these findings into clinical practice.

It has been reported that cancer cells get protected by a complex and rich multicellular environment i.e. the tumor microenvironment (TME) consisting of varying immune cells, endothelial cells, dendritic cells, fibroblasts, etc. This manuscript is aimed at the characteristic features of TME considered as potential target(s) for developing smart anticancer hydrogels.

The stimuli-specific drug delivery systems especially hydrogels that can respond to the characteristic features of TME are fabricated for treating cancer. For developing anticancer formulations, TME targeting can be considered an alternative way as it enhances the cytotoxic potential and reduces the unwanted effects. This manuscript shall be of quite interest to academicians, researchers, and clinicians engaged in oncology.

The manuscript was prepared by using the data available in the public domain in online resources such as Google Scholar, PubMed, Science Direct, Scopus, Web of Science, Research Gate, etc.

Smart hydrogels, sensitive to some specific features of TME such as low pH, high concentration of glutathione, specific enzymes, etc., are promising anticancer formulations as these improve the efficacy and lower the side effects of chemotherapy.

The stimuli-responsive hydrogels have been gaining more attention for delivering cytotoxic drugs to the TME in response to specific stimuli. The stimuli-responsive hydrogels, comprising of cytotoxic drug(s) and specific polymers have some special features such as similarity with biological matrix, ability to respond to various internal as well as external stimuli, improved permeability, porosity, biocompatibility, resemblance with soft living tissues, etc.; and are considered as the promising anticancer candidates.

Endometrial cancer (EC) is a worldwide gynecologic malignancies, with a remarking increase of incidence and mortality rates in recent years. Growing evidence indicates that glucose metabolism reprogramming is the most representative metabolic signature of tumor cells and exploring its modulatory function in EC development will promote identifying potential EC therapeutic targets. IGFBP2 is an insulin-like growth factor binding protein which is closely associated with a variety of metabolic diseases. However, its biological role in EC and its effects on glucose metabolism remain unclear. In this study, we demonstrated that IGFBP2 was highly expressed in EC tissues and correlated with poor prognosis. Overexpression of IGFBP2 promoted proliferation and glycolysis in EC cells, whereas IGFBP2 knockdown had the opposite effect. Mechanistically, IGFBP2 directly interacted with PKM2, inducing weakened PKM2 protein degradation, and knockdown IGFBP2 expression prevented the translocation of PKM2 to the nucleus. Additionally, IGFBP2 expression was upregulated under the condition of hypoxia which directly regulated by transcriptional activation of HIF-1α. Finally, the role of the IGFBP2/PKM2/HIF-1α axis in EC tumor growth was confirmed in vivo using mouse xenograft models. Taken together, the current study identifies IGFBP2 as an upstream activator of PKM2-driven proliferation and glycolysis in EC cells, providing a promising therapeutic target for EC.

This study aimed to investigate how Tanshinone IIA (Tan IIA) affects gastric cancer cell (MGC803) proliferation under anaerobic conditions, which are linked to drug resistance and tumor growth. The proliferation of MGC803 cells under both aerobic and anaerobic conditions in response to Tan IIA was assessed using the Cell Counting Kit-8 (CCK-8) assay. To elucidate the molecular mechanisms underlying these effects, proteomics analysis was performed following treatment with 50 µmol/L Tan IIA, focusing on alterations in Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Additionally, in vitro evaluations such as glucose uptake, lactate production, and adenosine triphosphate (ATP) synthesis were employed to validate the alterations in glycolytic activity observed in anaerobic cells treated with Tan IIA. Under anaerobic conditions, Tan IIA enhanced the inhibitory effect on the proliferation of MGC803 cells. Proteomics data revealed that a total of 6629 proteins were identified and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS), with 2604 proteins exhibiting significant changes (fold change > 2 or < 0.5, P < 0.05). KEGG analysis highlighted the perturbation of glycolytic pathway by Tan IIA under anaerobic conditions, accompanied by reduced glucose uptake, lactate production, and ATP synthesis. Additionally, a downregulation of glycolytic enzyme expression was observed at both the mRNA and protein levels, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase A (LDHA), phosphofructokinase 2 (PFKP), and pyruvate dehydrogenase (PDH). Tan IIA inhibits the proliferation of MGC803 cells by disrupting the glycolysis under anaerobic conditions, offering a potential treatment for anaerobiosis-resistant solid tumors.

Melanoma is an aggressive cancer with rising incidence and high mortality rates, largely due to chemotherapy resistance and molecular dysregulation. Nanotechnology, particularly silver nanoparticles (AgNPs), has emerged as a promising therapeutic avenue because of the nanoparticles' ability to induce oxidative stress and apoptosis in cancer cells. However, conventional colloidal AgNPs lack selectivity, often causing significant damage to healthy cells. In this study, we introduce a green synthesis of AgNPs using plant extracts, providing an eco-friendly alternative with improved antitumor selectivity compared to traditional colloidal AgNPs. Leveraging label-free Data-Independent Acquisition/Sequential Window Acquisition of All Theoretical Mass Spectrometry (DIA/SWATH MS) quantitative proteomics, we investigated the antitumor effects of green-synthesized versus traditional AgNPs on A375 melanoma cells at 24 and 48 h. Our findings reveal that green AgNPs selectively reduced melanoma cell viability while sparing healthy keratinocytes (HaCaT), a benefit not observed with colloidal AgNPs. Proteomic analysis highlighted that green AgNPs significantly downregulated oncogenes, enhanced carbohydrate metabolism, and disrupted copper homeostasis in melanoma cells. This marks the first study to explore the differential effects of green and traditional AgNPs on melanoma using an integrated proteomic approach, underscoring the molecular potential of green AgNPs as a targeted and sustainable option for cancer therapy.

Over the years, numerous ligand-based organotin(IV) Schiff base compounds have shown remarkable cytotoxicity and anticancer activities, but their clinical use is restricted by systemic toxicity, prompting the search for targeted therapies. Targeted delivery can be enhanced by exploiting the inherent characteristics of cancer cells such as glutamine addiction, which is essential to support cellular biosynthesis and cell growth to sustain aberrant proliferation. Our previous study revealed glutamine-conjugated organotin(IV) compounds have strong DNA/protein affinities, favorable in silico ADME profiles, and significant antiproliferative activity. In this study, these compounds demonstrated significant cytotoxicity against human colon carcinoma and adenocarcinoma cell lines via the induction of cell cycle arrest and apoptosis. In DMH/DSS-induced experimental colon carcinogenesis, these compounds reduced tumor burden and volume and inhibited cell proliferation and induced apoptosis, with minimal toxicity. Tissue distribution studies revealed selective accumulation in the colon. These findings support their potential as chemotherapeutic candidates for colon cancer.

Metabolic reprogramming within the tumor microenvironment (TME) plays a critical role in driving drug resistance in gastrointestinal cancers (GI), particularly through the pathways of fatty acid oxidation and glycolysis. Cancer cells often rewire their metabolism to sustain growth and reshape the TME, creating conditions such as nutrient depletion, hypoxia, and acidity that impair antitumor immune responses. Immune cells within the TME also undergo metabolic alterations, frequently adopting immunosuppressive phenotypes that promote tumor progression and reduce the efficacy of therapies. The competition for essential nutrients, particularly glucose, between cancer and immune cells compromises the antitumor functions of effector immune cells, such as T cells. Additionally, metabolic by-products like lactate and kynurenine further suppress immune activity and promote immunosuppressive populations, including regulatory T cells and M2 macrophages. Targeting metabolic pathways such as fatty acid oxidation and glycolysis presents new opportunities to overcome drug resistance and improve therapeutic outcomes in GI cancers. Modulating these key pathways has the potential to reinvigorate exhausted immune cells, shift immunosuppressive cells toward antitumor phenotypes, and enhance the effectiveness of immunotherapies and other treatments. Future strategies will require continued research into TME metabolism, the development of novel metabolic inhibitors, and clinical trials evaluating combination therapies. Identifying and validating metabolic biomarkers will also be crucial for patient stratification and treatment monitoring. Insights into metabolic reprogramming in GI cancers may have broader implications across multiple cancer types, offering new avenues for improving cancer treatment.

Glycolysis, present in most organisms, is evolutionarily one of the oldest metabolic pathways. It has great relevance at a physiological level because it is responsible for generating ATP in the cell through the conversion of glucose into pyruvate and reducing nicotinamide adenine dinucleotide (NADH) (that may be fed into the electron chain in the mitochondria to produce additional ATP by oxidative phosphorylation), as well as for producing intermediates that can serve as substrates for other metabolic processes. Glycolysis takes place through 10 consecutive chemical reactions, each of which is catalysed by a specific enzyme. Although energy transduction by glucose metabolism is the main function of this pathway, involvement in virulence, growth, pathogen-host interactions, immunomodulation and adaptation to environmental conditions are other functions attributed to this metabolic pathway. In humans, where glycolysis occurs mainly in the cytosol, the mislocalization of some glycolytic enzymes in various other subcellular locations, as well as alterations in their expression and regulation, has been associated with the development and progression of various diseases. In this review, we describe the role of glycolytic enzymes in the pathogenesis of diseases of clinical interest. In addition, the potential role of these enzymes as targets for drug development and their potential for use as diagnostic and prognostic markers of some pathologies are also discussed.

The clinical translation of positron emission tomography (PET) radiotracers for cancer management presents complex challenges. We have developed consensus-based recommendations for preclinical and clinical assessment of novel and established radiotracers, applied to image different cancer types, to improve the standardisation of translational methodologies and accelerate clinical implementation.

A consensus process was developed using the RAND/UCLA Appropriateness Method (RAM) to gather insights from a multidisciplinary panel of 38 key stakeholders on the appropriateness of preclinical and clinical methodologies and stakeholder engagement for PET radiotracer translation. Panellists independently completed a consensus survey of 57 questions, rating each on a 9-point Likert scale. Subsequently, panellists attended a consensus meeting to discuss survey outcomes and readjust scores independently if desired. Survey items with median scores ≥ 7 were considered 'required/appropriate', ≤ 3 'not required/inappropriate', and 4-6 indicated 'uncertainty remained'. Consensus was determined as ~ 70% participant agreement on whether the item was 'required/appropriate' or 'not required/not appropriate'.

Consensus was achieved for 38 of 57 (67%) survey questions related to preclinical and clinical methodologies, and stakeholder engagement. For evaluating established radiotracers in new cancer types, in vitro and preclinical studies were considered unnecessary, clinical pharmacokinetic studies were considered appropriate, and clinical dosimetry and biodistribution studies were considered unnecessary, if sufficient previous data existed. There was 'agreement without consensus' that clinical repeatability and reproducibility studies are required while 'uncertainty remained' regarding the need for comparison studies. For novel radiotracers, in vitro and preclinical studies, such as dosimetry and/or biodistribution studies and tumour histological assessment were considered appropriate, as well as comprehensive clinical validation. Conversely, preclinical reproducibility studies were considered unnecessary and 'uncertainties remained' regarding preclinical pharmacokinetic and repeatability evaluation. Other consensus areas included standardisation of clinical study protocols, streamlined regulatory frameworks and patient and public involvement. While a centralised UK clinical imaging research infrastructure and open access federated data repository were considered necessary, there was 'agreement without consensus' regarding the requirement for a centralised UK preclinical imaging infrastructure.

We provide consensus-based recommendations, emphasising streamlined methodologies and regulatory frameworks, together with active stakeholder engagement, for improving PET radiotracer standardisation, reproducibility and clinical implementation in oncology.

Initially, it was believed that glycolysis and DNA damage repair (DDR) were two distinct biological processes that independently regulate tumor progression. The former metabolic reprogramming rapidly generates energy and generous intermediate metabolites, supporting the synthetic metabolism and proliferation of tumor cells. While the DDR plays a pivotal role in preserving genomic stability, thus resisting cellular senescence and cell death under both physiological and radio-chemotherapy conditions. Recently, an increasing number of studies have shown closely correlation between these two biological processes, and then promoting tumor progression. For instance, lactic acid, the product of glycolysis, maintains an acidic tumor microenvironment that not only fosters cell proliferation and invasion but also facilitates DDR by enhancing AKT activity. Here, we provide a comprehensive overview of the enzymes and metabolites involved in glycolysis, along with the primary methods for DDR. Meanwhile, this review explores existing knowledge of glycolysis enzymes and metabolites in regulating DDR. Moreover, considering the significant roles of glycolysis and DDR in tumor development and radio-chemotherapy resistance, the present review discusses effective direct or indirect therapeutic strategies targeted to glycolysis and DDR.

Sodium glucose co-transporter 2 (SGLT2) inhibitors represent a novel class of hypoglycemic drugs that have emerged in recent years. These inhibitors function primarily by blocking the reabsorption of glucose in the kidneys, specifically targeting the SGLT2 proteins in the proximal convoluted tubules. This inhibition results in the reduction of blood glucose levels through increased glucose excretion in the urine. Recent studies have identified SGLT2 expression in various cancer types, suggesting that SGLT2 inhibition can potentially suppress tumor growth. This article provides a comprehensive review of the role of SGLT2 in tumorigenesis and tumor progression, and explores the underlying mechanisms and potential therapeutic applications of SGLT2 inhibitors as anticancer agents.

Comprehensively mapping the hierarchical structure of breast cancer protein communities and identifying potential biomarkers from them is a promising way for breast cancer research. Existing approaches are subjective and fail to take information from protein sequences into consideration. Deep learning can automatically learn features from protein sequences and protein-protein interactions for hierarchical clustering.

Using a large amount of publicly available proteomics data, we created a hierarchical tree for breast cancer protein communities using a novel hierarchical graph neural network, with the supervision of gene ontology terms and assistance of a pre-trained deep contextual language model. Then, a group-lasso algorithm was applied to identify protein communities that are under both mutation burden and survival burden, undergo significant alterations when targeted by specific drug molecules, and show cancer-dependent perturbations. The resulting hierarchical map of protein communities shows how gene-level mutations and survival information converge on protein communities at different scales. Internal validity of the model was established through the convergence on BRCA2 as a breast cancer hotspot. Further overlaps with breast cancer cell dependencies revealed SUPT6H and RAD21, along with their respective protein systems, HOST:37 and HOST:861, as potential biomarkers. Using gene-level perturbation data of the HOST:37 and HOST:861 gene sets, three FDA-approved drugs with high therapeutic value were selected as potential treatments to be further evaluated. These drugs include mercaptopurine, pioglitazone, and colchicine.

The proposed graph neural network approach to analyzing breast cancer protein communities in a hierarchical structure provides a novel perspective on breast cancer prognosis and treatment. By targeting entire gene sets, we were able to evaluate the prognostic and therapeutic value of genes (or gene sets) at different levels, from gene-level to system-level biology. Cancer-specific gene dependencies provide additional context for pinpointing cancer-related systems and drug-induced alterations can highlight potential therapeutic targets. These identified protein communities, in conjunction with other protein communities under strong mutation and survival burdens, can potentially be used as clinical biomarkers for breast cancer.

The impact of the dietary macronutrient composition and its subcomponents (saccharides, fatty acids, and protein sources) on radiation-induced acute skin toxicity (AST) in breast cancer (BC) patients is unknown. Hence, we examined the association between dietary macronutrients and their subcomponents and the risk of ≥grade 2 (G2) AST post-radiotherapy among women with BC.

An observational study was conducted among 161 BC patients treated with radiotherapy and enrolled in the ATHENA project in Italy. Habitual dietary intake was assessed at study entry (T0) using a 188-item food frequency questionnaire (FFQ). AST was measured at T1 (after 3 or 5 weeks of radiotherapy) and defined according to the Radiation Therapy Oncology Group criteria. A prospective analysis used multivariable-adjusted logistic regression models to examine the association between the dietary macronutrient composition and its subcomponents at T0 and the odds of ≥G2 AST post-radiotherapy.

≥G2 AST post-radiotherapy was observed in 43 (27%) patients. Among dietary macronutrient models, a higher intake of dietary carbohydrates was positively associated with a 30% higher odds of ≥G2 AST post-radiotherapy (OR = 1.30; 95% CI 1.01 to 1.67; for 30 g/d). Conversely, a higher dietary protein intake was inversely associated with a 76% lower odds of ≥G2 AST post-radiotherapy (OR = 0.24; 95% CI 0.06 to 0.91; for 30 g/d). There was no association with dietary fat. In macronutrient subcomponent models, only animal protein was inversely associated with a 51% lower odds of ≥G2 AST post-radiotherapy (0.49; 95% CI 0.25 to 0.95; for 15 g/d).

Dietary carbohydrates were associated with a higher risk of radiation-induced AST among women with BC, whereas dietary protein, especially animal protein, was associated with a lower risk. Cautiously balancing carbohydrate and protein intakes could be a part of the clinical management strategy for ≥G2 AST reduction post-radiotherapy among BC women.

Among women, breast cancer is one of the most prevalent cancers. The disease has a complex etiology, with multiple biological pathways contributing to its development. As insulin signaling has mitogenic effects, glucose is a necessary cellular metabolic substrate, and the growth and metastasis of breast cancer are closely related to cellular glucose metabolism. Anti-diabetic medications have drawn increased attention as a potential treatment for breast cancer. Metformin lowers cancer incidence and death rates in patients with type 2 diabetes, according to epidemiologic studies. Preclinical studies conducted in vivo and in vitro offer fascinating new insights into the cellular mechanisms underlying metformin oncostatic action. We present an overview of the mechanisms of anticancer effects of metformin and discuss its potential function as an adjuvant in the treatment of breast cancer.

Dysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukemia (AML) RBPs are key regulators of tumor proliferation. While classical RBPs have defined RNA binding domains, RNA recognition and function in AML by non-canonical RBPs (ncRBPs) remain unclear. Given the inherent complexity of targeting AML broadly, our goal was to uncover potential ncRBP candidates critical for AML survival using a CRISPR/Cas-based screening. We identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a pro-proliferative factor in AML cells. Based on cross-linking and immunoprecipitation (CLIP), we are defining the global targetome, detecting novel RNA targets mainly located within 5'UTRs, including GAPDH, RPL13a, and PKM. The knockdown of GAPDH unveiled genetic pathways related to ribosome biogenesis, translation initiation, and regulation. Moreover, we demonstrated a stabilizing effect through GAPDH binding to target transcripts including its own mRNA. The present findings provide new insights on the RNA functions and characteristics of GAPDH in AML.

Protein post translational modification (PTM) is the main regulatory mechanism for eukaryotic cell function, among which ubiquitination is based on the reversible degradation of proteins by the ubiquitin proteasome system to regulate cell homeostasis. The neural precursor cell expressed developmental downregulated gene 8 (NEDD8) is a kind of ubiquitin like protein that shares 80 % homology and 60 % identity with ubiquitin. The PTM process by covalently binding NEDD8 to lysine residues in proteins is called neddylation. The neddylation reaction could be regulated by NEDD8, its precursors, substrates, E1 activating enzymes, E2 binding enzymes, E3 ligases, de-neddylases, and its inhibitors, such as MLN4924. NEDD8 is widely expressed in the whole cell structure of multiple tissues and species, and neddylation related factors are highly expressed in metabolism related adrenal glands, thyroid glands, parathyroid glands, skeletal muscles, myocardium, and adipose tissues, related to metabolic cardiovascular, cerebrovascular and liver diseases, adipogenic and osteogenic differentiation, as well as tumor glycolysis and glucose metabolism resulting from angiogenesis and endothelial disfunction, hepatotoxicity, adipogenesis, osteogenesis, Warburg effect, and insulin function. This review provides researchers with a new approach to explore metabolic diseases via searching and analyzing the histological, cytological, and subcellular localization of neddylation specific molecules in databases, and exploring specific mechanism neddylation mediating metabolic diseases by searching for neddylation related terms with the development of pre-clinical neddylation pharmacological inhibitors.

Cancer incidence has increased globally and has become the leading cause of death in the majority of countries. Many cancers have altered energy metabolism pathways, such as increased glucose uptake and glycolysis, as well as decreased oxidative phosphorylation. This is known as the Warburg effect, where cancer cells become more reliant on glucose to generate energy and produce lactate as an end product, even when oxygen is present. These are attributed to the overexpression of key glycolytic enzymes, glucose transporters, and related signaling pathways that occur in cancer cells. Therefore, overcoming metabolic alterations in cancer cells has recently become a target for therapeutic approaches. Natural products have played a key role in drug discovery, especially for cancer and infectious diseases. In this review, we are going to focus on terpenoids, which are gradually gaining popularity among drug researchers due to their reported anti-cancer effects via cell cycle arrest, induction of apoptosis, reduction of proliferation, and metastasis. This review summarizes the potential of 13 terpenoid compounds as anti-glycolytic inhibitors in different cancer models, primarily by inhibiting the glucose uptake and the generation of lactate, as well as by downregulating enzymes associated to glycolysis. As a conclusion, disruption of cancer cell glycolysis may be responsible for the anti-cancer activity of terpenoids.

Aerobic glycolysis is one of the major hallmarks of malignant tumors. This metabolic reprogramming benefits the rapid proliferation of cancer cells, facilitates the formation of tumor microenvironment to support their growth and survival, and impairs the efficacy of various tumor therapies. Therefore, the elucidation of the mechanisms driving aerobic glycolysis in tumors represents a pivotal breakthrough in developing therapeutic strategies for solid tumors. HIF1α serves as a central regulator of aerobic glycolysis with elevated mRNA and protein expression across multiple tumor types. However, the mechanisms contributing to this upregulation remain elusive. This study reports the identification of a novel HIF1α super enhancer (HSE) in multiple cancer cells using bioinformatics analysis, chromosome conformation capture (3C), chromatin immunoprecipitation (ChIP), and CRISPR/Cas9 genome editing techniques. Deletion of HSE in cancer cells significantly reduces the expression of HIF1α, glycolysis, cell proliferation, colony and tumor formation ability, confirming the role of HSE as the enhancer of HIF1α in cancer cells. Particularly, we demonstrated that STAT3 promotes the expression of HIF1α by binding to HSE. The discovery of HSE will help elucidate the pathways driving tumor aerobic glycolysis, offering new therapeutic targets and potentially resolving the bottleneck in solid tumor treatment.

Cancer ranks among the primary contributors to global mortality. In 2022, the global incidence of new cancer cases reached about 20 million, while the number of cancer-related fatalities reached 9.7 million. In Saudi Arabia, there were 13,399 deaths caused by cancer and 28,113 newly diagnosed cases of cancer. Drug repurposing is a drug discovery strategy that has gained special attention and implementation to enhance the process of drug development due to its time- and money-saving effect. It involves repositioning existing medications to new clinical applications. Cancer treatment is a therapeutic area where drug repurposing has shown the most prominent impact. This review presents a compilation of medications that have been repurposed for the treatment of various types of cancers. It describes the initial therapeutic and pharmacological classes of the repurposed drugs and their new applications and mechanisms of action in cancer treatment. The review reports on drugs from various pharmacological classes that have been successfully repurposed for cancer treatment, including approved ones and those in clinical trials and preclinical development. It stratifies drugs based on their anticancer repurpose as multi-type, type-specific, and mechanism-directed, and according to their pharmacological classes. The review also reflects on the future potential that drug repurposing has in the clinical development of novel anticancer therapies.

Biological applications of sumanene buckybowl molecule have been widely discussed over the years yet remain still unexplored experimentally. On the other hand, creating cyclodextrin-containing supramolecular assemblies was demonstrated to be a powerful tool in terms of designing effective systems for medicinal chemistry purposes. Here, we show that sumanene molecule exclusively forms 1:1 host-guest complexes with γ-cyclodextrin (γCD) or (2-hydroxypropyl)-γ-cyclodextrin (HP-γCD), as revealed by extensive spectroscopic studies supported with density functional theory (DFT) computations. Based on our preliminary biological studies, we discovered that the formation of such complexes resulted in the improvement of anticancer properties of sumanene, expressed by high cell viabilities in vitro of healthy human mammary fibroblasts (HMF) together with low viabilities of human breast adenocarcinoma cells (MDA-MB-231). Improved pharmacokinetic (ADME-Tox) properties for sumanene@γCD and sumanene@HP-γCD complexes in comparison to native sumanene were also supported by in sillico modeling studies. This work provides the method how to focus the cytotoxic action of sumanene toward cancer cells using supramolecular assembly strategy, paving the way to the further exploration of biological properties of sumanene-containing supramolecular systems with bioactive features and applications of this buckybowl in general.

Sepsis-induced acute lung injury (SALI) is characterized by a high incidence and mortality rate, which has caused a serious medical burden. The pharmacological effects of esculetin (ELT), such as antibacterial and anti-inflammatory actions, have been widely confirmed. However, the therapeutic effects and mechanisms of ELT on SALI still need to be further clarified. In this study, we first evaluated the therapeutic potential of ELT on a caecal ligation and puncture (CLP) induced septic rat model, particularly in the treatment of acute lung injury. Afterwards, we explored the effect of ELT on macrophage polarization in vivo and in vitro. Then, we investigated the anti-inflammatory mechanism of ELT based on modulating the metabolic reprogramming of macrophage (the effect on glycolysis in M1, and the effect on fatty acid β-oxidation in M2). In addition, macrophage metabolic inhibitors (glycolysis inhibitor: 2-DG, and fatty acid β-oxidation inhibitor: etomoxir) were used to verify the regulatory effect of ELT on macrophage metabolic reprogramming. Our results proved that ELT intervention could effectively improve the survival rate of SALI rats and ameliorate pathological injury. Next, we found that ELT intervention inhibited M1 polarization and promoted M2 polarization of macrophages in vivo and in vitro, including the downregulation of M1-related markers (CD86, iNOS), the decrease of pro-inflammatory factors (nitric oxide, IL-1β, IL-6, and TNF-α), the upregulation of M2-related markers (CD206, ARG-1), the increase of immunomodulatory factors (IL-4 and IL-10). Subsequently, seahorse analysis showed that ELT intervention inhibited the glycolytic capacity in M1, and promoted the ability of fatty acid β-oxidation in M2. Besides, ELT intervention inhibited the level of glycolysis product (lactic acid), and the expression of glycolysis-related genes (Glut1, Hk2, Pfkfb1, Pkm and Ldha) and promoted the expression of fatty acid β-oxidation related genes (Cpt1a, Cpt2, Acox1). In addition, we found that the inhibitory effect of ELT on M1 polarization was comparable to that of 2-DG, while intervention with etomoxir abolished the promoting effect of ELT on M2 polarization. ELT inhibited the inflammatory response in SALI by correcting macrophage polarization (inhibiting M1 and promoting M2). The mechanism of ELT on macrophage polarization was associated with regulating metabolic reprogramming (inhibiting glycolysis in M1 and promoting fatty acid β-oxidation in M2).

Aging is a complex biological process characterized by the gradual decline of cellular functions, increased susceptibility to diseases, and impaired stress responses. Hypoxia, defined as reduced oxygen availability, is a critical factor that influences aging through molecular pathways involving hypoxia-inducible factors (HIFs), oxidative stress, inflammation, and epigenetic modifications. This review explores the interconnected roles of hypoxia in aging, highlighting how hypoxic conditions exacerbate cellular damage, promote senescence, and contribute to age-related pathologies, including cardiovascular diseases, neurodegenerative disorders, cancer, metabolic dysfunctions, and pulmonary conditions. By examining the molecular mechanisms linking hypoxia to aging, we identify key pathways that serve as potential therapeutic targets. Emerging interventions such as HIF modulators, antioxidants, senolytics, and lifestyle modifications hold promise in mitigating the adverse effects of hypoxia on aging tissues. However, challenges such as the heterogeneity of aging, lack of reliable biomarkers, and safety concerns regarding hypoxia-targeted therapies remain. This review emphasizes the need for personalized approaches and advanced technologies to develop effective antiaging interventions. By integrating current knowledge, this review provides a comprehensive framework that underscores the importance of targeting hypoxia-induced pathways to enhance healthy aging and reduce the burden of age-related diseases.

Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise in improving CAR T cells for the treatment of solid tumors.

Glucose is an important energy source for tumors, however the molecular mechanisms by which tumor cells regulate glucose uptake remain unclear. In this study, we aimed to investigate the regulation mechanism of the WNT7B/β-catenin pathway for glucose transporter 1 (GLUT1)-mediated glucose metabolism in colorectal cancer. Here, we found that WNT7B expression levels were significantly increased in colorectal cancer tissues and closely associated with the clinical stage and lymph node metastasis in patients with colorectal cancer. Next, we confirmed that WNT7B significantly increased the glucose consumption and lactic acid levels in SW480 cells by overexpressing WNT7B. Additionally, gene and protein levels of GLUT1 were increased in WNT7B-overexpressing SW480 cells. However, WNT7B knockdown reversed these effects. WNT7B also enhanced GLUT1-mediated cell proliferation, invasion, and migration. WNT7B overexpression inhibited the effect of glucose deprivation on apoptosis. The WNT/β-catenin signaling pathway inhibitor, LGK974, inhibited WNT7B secretion, leading to GLUT1 levels downregulation and promotion of cell apoptosis. Ectopic tumor xenograft model experiments revealed that WNT7B promoted tumor progression in mice. Overall, our results suggest that WNT7B promotes β-catenin entry into the nucleus to initiates GLUT1 transcription, increases glucose transport and consumption, and enhances aerobic glycolysis, thus promoting tumor progression in colorectal cancer cells.