Glufosinate-ammonium (GLA) is a widely used organophosphorus herbicide, which poses a potential threat to non-target aquatic species. This study aimed to evaluate the toxic effects of acute exposure to GLA on the hepatopancreas of juvenile Eriocheir sinensis, and to preliminarily reveal the toxicity mechanism. The results showed that the 96h-LC50 of GLA on juvenile E. sinensis was 386.61 mg/L. The acute test showed that GLA exposure caused hepatopancreas histological lesions, DNA damage and a higher apoptosis rate. The activities of aspartate aminotransferase and alanine aminotransferase in serum increased significantly and had a concentration-dependent effect. Moreover, GLA exposure resulted in a significant increase in malondialdehyde content, which subsequently activated the antioxidant system and detoxification system, and the related enzyme activities and gene expression levels were significantly increased. In addition, the RNA-Seq analysis showed that the toxic effects of GLA exposure on juvenile crabs may mainly involve physiological pathways such as energy metabolism, protein synthesis and nervous system function. This study highlights the hepatotoxic effects of GLA on aquatic crustaceans and preliminarily reveals the key pathways of action. The results of this study will helpful to provide new insights into the toxic effects and risk assessment of herbicides on non-target organisms.

Novel lipophilic cationic derivatives including quaternary ammonium salt and triphenylphosphine series were designed and synthesized using diosgenin (1) and sarsasapogenin (2) as substrates to improve the cytotoxicity and selectivity. Most of the derivatives showed higher cytotoxicity against all cancer cell lines tested, compound 13 exhibited the most superior activity against A549 cells with an IC50 value of 0.95 μM, which was 34-fold of diosgenin. Preliminary cellular mechanism studies elucidated that compound 13 might arrest cell cycle at G0/G1 phase, trigger apoptosis via up-regulating the expression of Bax, down-regulating the expression of Bcl-2 and caspase-3, and induce an increase in the generation of intracellular reactive oxygen species (ROS) in A549 cells. In addition, molecular docking analysis revealed that compound 13 could occupy the active site of p38α-MAPK well and interact to the surrounding amino acids by salt bridge and conjugation. These results suggested that compound 13 had the potential to serve as an antitumor lead agent, probably exert antitumor effect through mitochondrial pathway and p38α MAPK pathway.

Lymphoma is a common cancer of the lymphatic system, and its treatment presents considerable clinical difficulties due to the constraints of existing medicines. Anticancer drug such as Doxorubicin (DOX) is an effective chemotherapeutic drug that is frequently used to treat lymphoma and other cancers; however, it is linked with considerable toxicities. Fisetin, a naturally occurring flavonoid, exhibits anticancer properties and has the potential to augment the therapeutic effects of DOX. This study explores the synergistic effects of combining DOX with fisetin in the treatment of lymphoma. The combination of DOX and fisetin significantly inhibits cell viability, induced membrane blabbing, chromatin condensation, and promoted apoptosis compared to monotherapies. The study also showed that the synergistic effect of fisetin along with DOX significantly promotes apoptosis in DL cells through intracellular ROS generation, mitochondrial aggregation at the periphery of the nucleus and, increased p53, Bax, cytochrome c, caspase 3, caspase 9, and cleaved caspase 9 expression. Additionally, combination therapy not only increased the mean survival of the treated group animals but also reduced the tumor burden. While histopathological parameters have shown overall improvement in combination therapy. This study proposes a novel combinational therapy for the treatment of lymphoma and requires further clinical investigation.

Drug resistance in cancer poses a serious challenge in finding an effective remedy for cancer patients, because of the multitude of contributing factors influencing this complex phenomenon. One way to counter this problem is using a more targeted and dose-limiting approach for drug delivery, rather than relying on conventional therapies that exhibit multiple pernicious side-effects. Stability and specificity have traditionally been the core issues of peptide-based delivery vectors. In this study, we employed a structural regression modelling approach in the design, synthesis and characterization of a series of peptides that belong to approximately same topological cluster, yet with different electrostatic signatures encoded as a result of their differential positioning of amino acids in a given sequence. The peptides tagged with the fluorophore 5(6)-carboxyfluorescein, showed higher uptake in cancer cells with some of them colocalizing in the lysosomes. The peptides tagged with the anti-cancer drug methotrexate have displayed enhanced cytotoxicity and inducing apoptosis in triple-negative breast cancer cells. They also showed comparable uptake in side-population cells of lung cancer with stem-cell like properties. The most-optimized peptide showed accumulation in the tumor resulting in significant reduction of tumor size, compared to the untreated mice in in-vivo studies. Our results point to the following directives; (i) peptides can be design engineered for targeted delivery (ii) stereochemical engineering of peptide main chain can resist proteolytic enzymes and (iii) cellular penetration of peptides into cancer cells can be modulated by varying their electrostatic signatures.

Abnormal tumor metabolism leads to tumor growth, metastasis, and recurrence, reprogramming tumor metabolism and activating potent anti-tumor immune response have been demonstrated to have good therapeutic effects on tumor elimination. Copper-based nanomaterials involved in cuproptosis show great prospects in these two aspects, but their efficiency is restricted by Cu homeostasis and the toxicity of the chelator. Here, the pH-responsive AuNRs@Cu2O core-shell plasmonic hybrid nanorods (ACNRs) have been successfully fabricated to realize microenvironment-controlled release at the tumor site for the combined therapy of cuproptosis and photothermal treatment. The AuNRs core exhibited excellent NIR-II photothermal property, which boost the intracellular concentration of copper to trigger severe cuproptosis and induce immunogenic cell death of tumor cells. In vivo studies demonstrated the ACNR exhibited efficient tumor therapy for primary, metastatic, and recurrent tumors. ACNRs-induced cuproptosis and PTT were capable of reprogramming energy metabolism, leading to a decreased production of lactic acid. This potential of metabolic reprogramming assisted in reshaping the immunosuppressive tumor microenvironment to facilitate the infiltration of immune cells and boost the immune responses triggered by PTT. The therapeutic mechanism was further verified by metabolomics analysis, which indicated that ACNRs + PTT treatment led to the inhibition of the Pentose Phosphate Pathway and Glycolysis pathways in tumor cells. The suppression of glycolytic reduced ATP synthesis, thereby hindering energy-dependent copper efflux, which in turn promoted cuproptosis. Taken together, this study offers promising insights for cuproptosis-based cancer treatment and sheds new light on nanomedicine-mediated metabolic modulation for future tumor therapy.

The traditional medicinal plant Centella asiatica is commonly used in Chinese and Ayurvedic medicine due to its vast range of therapeutic properties. Previously, the ethanolic C. asiatica leaf extract was subjected to silica column fractionation, and the C3 fraction was obtained. We investigated the antioxidant and anti-proliferative effects of C3 in human embryonic kidney (HEK293) cells. In HEK293 cells, C3 cytotoxicity was assessed (viability assay; 24 h; [0.2-3 mg/mL]), and a half maximal inhibitory concentration (IC50) was determined. Malondialdehyde (MDA), lactate dehydrogenase (LDH) (spectrophotometry), mitochondrial depolarization (Δψm), intracellular reactive oxygen species (flow cytometry), glutathione (GSH), oxidized glutathione (GSSG) concentrations, caspase activities, ATP levels (luminometry), and fragmentation of DNA (SCGE assay) were evaluated. Protein expressions were assessed by western blotting. Gene expressions were quantified by qPCR. Cell viability in HEK293 cells was decreased in a dose-dependent manner by C3. MDA, Δψm, LDH, caspase activities, and DNA fragmentation (P < .0004) were significantly increased by C3. Nuclear factor erythroid 2-related factor 2 (Nrf-2) protein expression, GSH, and GSSG concentrations were increased, whereas antioxidant (Nrf-2, GPx, SOD, and CAT) gene expression was significantly decreased by C3 (P < .001). C3 decreased both Bax and Bcl-2 protein expression (P < .03). Gene expression of c-myc was significantly increased, whereas OGG-1 was significantly reduced by C3 (P < .05). C3 reduced antioxidant gene expression, increased antioxidant levels, and elevated anti-proliferative effects in HEK293 cells, suggesting that high concentrations of C3 are potentially toxic to kidney cells, thus rendering cause for concern with its human use.

Gastric cancer (GC) is a common malignancy with poor prognosis and lack of efficient therapeutic methods. Shen Qing Weichang Formula (SQWCF) is a patented traditional herbal prescription for GC, but its efficacy and underlying mechanism remains to be clarified.

To explore the efficacy and potential mechanism of SQWCF in treating GC.

A subcutaneous transplantation tumor model of human GC was established for assessing SQWCF's efficacy and safety. A comprehensive strategy integrating mass spectrometry, network pharmacology, omics analysis, and bioinformatic methods was adopted to explore the core components, key targets, and potential mechanism of SQWCF in treating GC. Molecular docking, immunohistochemistry, quantitative real-time PCR, and western blot were applied to validation.

In the mouse model of GC, SQWCF effectively suppressed the GC growth without evident toxicity and enhanced the therapeutic efficacy of paclitaxel. Network pharmacology and molecular docking based on mass spectrometry showed that key targets (CASP3, TP53, Bcl-2, and AKT1) and core active components (Calycosin, Glycitein, Liquiritigenin, Hesperetin, and Eriodictyol) involved in the anti-GC effect of SQWCF had stable binding affinity, of which AKT1 ranked the top in the affinity. Validation based on network pharmacology and omics analysis confirmed that PI3K-AKT and MAPK signaling pathways, as well as downstream apoptosis pathway, explained the therapeutic effects of SQWCF on GC. In addition, family with sequence similarity 81 member A (FAM81A) was identified as a novel biomarker of GC that was aberrantly highly expressed in GC and associated with poor prognosis by bioinformatic analysis, and was an effector target of SQWCF at both mRNA and protein levels.

This study uncovers a synergistic multi-component, multi-target, and multi-pathway regulatory mechanism of SQWCF in treating GC comprehensively, emphasizing its potential for therapeutic use and providing new insights into GC treatment.

X-linked inhibitor of apoptosis protein (XIAP) is the most potent endogenous member of the inhibitor of apoptosis protein family. XIAP exerts its anti-apoptotic effects by inhibiting both the death receptor pathway and mitochondrial pathway of apoptosis through various mechanisms such as directly binding to caspases, activating the nuclear factor kappa B (NF-κB) pathway, and other signaling pathways. These processes are closely related to tumor development and progression, making XIAP a therapeutic target for various types of cancer. This article will first review the structural characteristics and biological functions of XIAP, followed by its effects on tumors and an overview of XIAP-targeted inhibitors.

Colon cancer (CC) ranks is the second leading cause of cancer-related deaths globally. Despite chemotherapy being a primary treatment its effectiveness significantly declines in advanced in stage. Emerging evidence suggests that dietary components particularly polysaccharides, play a role in CC progression. This study employed multi-omics and network pharmacology to elucidate the mechanisms underlying the apoptotic effects of Caulerpa lentillifera polysaccharide (CLP) in CC, validated through in vitro and in vivo experiments. Transcriptomics and network pharmacology analysis identified the p53/Bax/Caspase-3 pathway as a key regulatory axis. Further targeted analysis of amino acid metabolism revealed that CLP significantly decreased intracellular aspartate (Asp) levels. Additionally, reactive oxygen species (ROS) accumulation was detected in cells. CLP treatment reduced Asp content, leading to ROS accumulation, which activated the p53/Bax/Caspase-3 pathway, triggering apoptosis. In vivo, CLP effectively inhibited tumor growth in BALB/c mice bearing CT26 colon cancer cells. These findings suggest that CLP exerts anti-colon cancer effects by modulating amino acid metabolism and inducing apoptosis via the p53/Bax/Caspase-3 axis, providing a promising therapeutic strategy for CC.

Diffuse large B-cell lymphoma (DLBC) is the most common subtype of non-Hodgkin lymphoma, characterized by its aggressive nature and poor prognosis in advanced stages. Despite advances in treatment, the molecular mechanisms driving DLBC progression remain incompletely understood, necessitating the identification of novel biomarkers for diagnosis and prognosis. In this study, we analyzed two publicly available datasets (GSE32018 and GSE56315) from the Gene Expression Omnibus database (GEO) to identify overlapping differentially expressed genes (DEGs). Later on, a comprehensive in silico and in vitro methodology was adopted to decipher the role of identify DEGs in DLBC. DEGs analysis of GSE32018 and GSE56315 datasets identified five overlapping gene: SP3, CSNK1A1, STYX, SIRT5, and MGEA5. Expression validation using the GEPIA2 database confirmed the upregulation of SP3, CSNK1A1, STYX, and SIRT5, and the downregulation of MGEA5 in DLBC tissues compared to normal controls. Furthermore, mutational analysis revealed that CSNK1A1 was the only gene among these DEGs to exhibit mutations, with a 2.7% mutation frequency in DLBC patients. Methylation analysis highlighted a negative correlation between DEGs methylation levels and mRNA expression, while survival analysis identified high STYX expression as significantly associated with poorer overall survival in DLBC patients. Functional assays demonstrated that STYX knockdown in U2932 cells led to reduced cell proliferation, colony formation, and enhanced wound healing, indicating STYX's pivotal role in DLBC cell survival and migration. Additionally, gene enrichment analysis revealed the involvement of these DEGs in key biological processes, including intracellular trafficking and myeloid progenitor cell differentiation. These findings emphasize the potential of SP3, CSNK1A1, STYX, SIRT5, and MGEA5 as biomarkers and therapeutic targets in DLBC, particularly highlighting STYX as a promising prognostic marker and potential target for therapeutic intervention.

MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. Among these, miR-660, located on chromosome Xp11.23, is increasingly studied for its role in cancer due to its abnormal expression in various biological contexts. It is regulated by 8 competing endogenous RNAs (ceRNAs), which adds complexity to its function. miR- 660 targets 19 genes involved in 6 pathways such as PI3K/AKT/mTOR, STAT3, Wnt/β-catenin, p53, NF‑κB, and RAS, influencing cell cycle, proliferation, apoptosis, and invasion/migration. It also plays a role in resistance to chemotherapies like cisplatin, gemcitabine, and sorafenib in lung adenocarcinoma (LUAD), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC), thus highlighting its clinical importance. Additionally, leveraging liposomes as nanocarriers presents a promising avenue for enhancing cancer drug delivery. Our comprehensive study not only elucidates the aberrant expression patterns, biological functions, and regulatory networks of miR-660 and its ceRNAs but also delves into the intricate signaling pathways implicated. We envisage that our findings will furnish a robust framework and serve as a seminal reference for future investigations of miR-660, fostering advancements in cancer research and potentially catalyzing breakthroughs in cancer diagnosis and treatment paradigms.

The traditional treatment for cervical cancer involves aggressive surgery combined with radiotherapy and chemotherapy. Nevertheless, these treatments have certain limitations and side effects, thus breakthroughs and advances are required in cervical cancer therapy. Magnesium alloy is a promising antitumor biomaterial with excellent biocompatibility and biodegradability. However, the potential effects of magnesium alloy on cervical tumors have not been extensively explored. Recent studies have demonstrated that adding a small amount of calcium to the magnesium matrix can reduce grain size and corrosion rate while providing good biocompatibility. We conductedin vivoandin vitroexperiments to test the antitumor properties of Mg-1%Ca alloys. The results indicated that the Mg-1%Ca alloy released Mg2+and OH-more slowly, inhibited the proliferation of SiHa and HeLa cells, induced apoptosis in tumor cells, disrupted the cytoskeleton, and inhibited cell migration and invasion. At the molecular level, Mg-1%Ca alloy significantly activated the mitochondrial apoptosis pathway and inhibited the MAPK/ERK signaling pathway. In the future, Mg-1%Ca may be employed in the treatment of cervical cancer as a novel adjuvant therapeutic material with anticancer function to prevent the occurrence and progression of cancer proliferation and metastasis.

The transcription factor MYB proto-oncogene like 2 (MYBL2) has been reported to be involved in the occurrence and development of various tumors, however, its role in gastric cancer (GC) remains to be elucidated. In this study, the Kaplan-Meier plotter was used to evaluate the prognostic value of different MYBL2 expression levels in GC patients. The UALCAN database were applied to analyze the relationships between MYBL2 and clinicopathological characteristics of GC. GC cell proliferation, cell cycle and apoptosis were determined by CCK-8 and flow cytometry assays, and proteins were examined by Western blot analysis. Next, signaling pathway enrichment analysis of MYBL2-related genes and protein expression were analyzed by Gene Set Enrichment Analysis (GSEA) and Western blot assays. The results found that MYBL2 expression was significantly upregulated in GC compared with adjacent non-malignant tissues and associated with poor patient survival, tumor, stages and lymph node metastasis. Forced expression of MYBL2 could promote cell proliferation, resulting in an accelerated S phase progression and inhibiting cell apoptosis in GC cells. Conversely, MYBL2 silencing inhibited cell proliferation, induced G2/M phase arrest and promoted cell apoptosis in GC cells. Mechanistically, Western blot analysis showed that MYBL2 silencing decreased the expression of BCL2 and upregulated the expression of Cleaved-caspase-3 and BAX in HGC-27 cells. Conversely, MYBL2 overexpression in AGS cells resulted in the opposite effects. Furthermore, enforced expression of MYBL2 activated the PI3K/AKT signaling pathway, especially AKT phosphorylation. Additionally, the AKT inhibitor MK2206 significantly reversed the proliferation capacity of GC cells induced by MYBL2 overexpression. Therefore, these results suggest that upregulated expression of MYBL2 contributes to GC cell growth and inhibits cell apoptosis by regulating the PI3K/AKT and BCL2/BAX/Cleaved-caspase-3 signaling pathways in GC cells indicating that MYBL2 may be a new therapeutic target and prognostic marker for GC.

Cancer stands as a formidable malady profoundly impacting human health. Throughout history, plant-based therapies have remained pivotal in the arsenal against cancer, evolving alongside the epochs. Presently, challenges such as the arduous extraction of active components and potential safety concerns impede the progression of plant-based anticancer therapies. The isolation of plant-derived vesicle-like nanoparticles (PDVLNs), a kind of lipid bilayer capsules isolated from plants, has brought plant-based anticancer therapy into a novel realm and has led to decades of research on PDVLNs. Accumulating evidence indicates that PDVLNs can deliver plant-derived active substances to human cells and regulate cellular functions. Regulating immunity, inducing cell cycle arrest, and promoting apoptosis in cancer cells are the most commonly reported mechanisms of PDVLNs in tumor suppression. Low immunogenicity and lack of tumorigenicity make PDVLNs a good platform for drug delivery. The molecules within the PDVLNs are all from source plants, so the selection of source plants is crucial. In recent years, there has been a clear trend that the source plants have changed from vegetables or fruits to medicinal plants. This review highlights the mechanisms of medicinal plant-based cancer therapies to identify candidate source plants. More importantly, the current research on PDVLN-based cancer therapy and the applications of PDVLNs for drug delivery are systematically discussed.

Radioresistance presents a major challenge in the treatment of cervical cancer (CC). Apoptotic tumor cells can create an "onco-regenerative niche," contributing to radioresistance. However, the intercellular signaling mechanisms mediating the transfer of radioresistance from apoptotic to surviving cancer cells remain unclear.

The role of apoptotic tumor cell-derived extracellular vesicles (apoEVs) in mediating radioresistance was investigated through integrated bioinformatics and experimental approaches. The GSE236738 dataset was analyzed to identify potential regulators, with subsequent validation of apoEV-MTA1 function using in vitro and in vivo models. Mechanistic studies focused on caspase-3 activation, p-STAT1 signaling pathway, and dormancy-associated protein networks. Furthermore, therapeutic strategies targeting MTA1 and its downstream signaling were evaluated for radiosensitization potential.

MTA1 was identified as a critical factor enriched in and transferred by apoEVs from apoptotic tumor cells to neighboring CC cells. Caspase-3 activation facilitated the nuclear export and encapsulation of MTA1 in apoEVs. Transferred MTA1 retained transcriptional activity, activated the p-STAT1 signaling pathway, and induced cellular dormancy via NR2F1, a key dormancy regulator, resulting in increased radioresistance. Knockdown of MTA1 in apoEVs or inhibition of p-STAT1 in recipient cells enhanced radiosensitivity. Furthermore, apoEV-MTA1 promoted tumor radioresistance and reduced survival rates in irradiated cervical cancer mouse model.

This study demonstrates that apoEV-MTA1 confers radioresistance in CC by promoting cellular dormancy via the p-STAT1/NR2F1 signaling axis. Targeting this pathway could improve radiosensitivity and provide a promising therapeutic strategy for CC patients.

Multiple myeloma (MM) is a common hematologic malignancy. Huachansu (HCS) is extracted from the skin of Bufo bufo gargarizans, known for its well-established and multi-target anti-tumor effect. It has been reported to be effective in treating patients with multiple myeloma but its underlying mechanism remains unclear.

This study aims to investigate the cellular and molecular mechanisms in which HCS induces cell death of MM.

Cell viability was assessed using the CCK-8 assay. The effect of HCS on the gene expression of MM were screened by transcriptome sequencing and validated by quantitative real-time PCR, Western blot, and immunofluorescence. The ferroptosis phenotype were evaluated by measuring iron ion concentration, lipid peroxidation degree in terms of malondialdehyde (MDA), and reduced glutathione (GSH) level. Flow cytometry was adopted to measure intracellular ROS and PGSK levels. The ability of ferroptosis inhibitors to reverse these effects was also assessed. The treatment effect and ferroptosis induction of HCS on MM in vivo were explored on a xenograft nude mice model, with mitochondrial damage observed by transmission electron microscopy.

HCS modulated the NRF2/HO-1 pathway, upregulating PRP and ZIP8, leading to Fe2+ accumulation and PGSK elevation, while increasing ROS and MDA levels and reducing GSH content. These effects were significantly reversed by the ferroptosis inhibitor Ferrostin-1. HCS induced MM cell ferroptosis through the NRF2/HO-1 pathway in vivo, inhibiting MM progression similarly to the positive control drug bortezomib.

These results indicate that HCS can induce ferroptosis in MM cells via the NRF2/HO-1 pathway, thereby controlling MM progression. Our study provides a solid theoretical basis for the clinical use of HCS in treating MM. Additionally, it suggests an innovative treatment alternative based on natural medicine, proposing the combined use of HCS and chemotherapy drugs as a new therapeutic avenue for MM.

Polycystic ovary syndrome (PCOS) is currently recognized as a condition that affects several systems in the body, including the reproductive, endocrine, and cardiovascular systems. Prevalent among teenagers and women of reproductive age. Prior research has demonstrated an elevation of miR-34a-5p within the follicular fluid (FF) of women of PCOS. Despite this, the precise mechanisms through which miR-34a-5p influences granulosa cells (GC) development and function remain poorly characterized.

Therefore, this study investigates the involvement and pathogenic mechanisms of miR-34a-5p within GCs in the context of PCOS. The human granulosa-like tumor cell line (KGN) got transfected at a control, as well as a miR-34a-5p mimic and inhibitor, respectively. Monitor cellular proliferation in each experimental group. The experimental methods included RT-qPCR, CCK8, flow cytometry and western blotting. Also, the interaction between miR-34a-5p and the particular sequence of JAG1 has been verified using the dual luciferase assay. Further investigation of the connection involving miR-34a-5p and the Notch signaling pathway was conducted using bioinformatics analysis and experimental methods.

The results demonstrated that miR-34a-5p expression was significantly elevated in the serum(p<0. 0001)and FF (p = 0. 0402) of PCOS, whereas its expression in GCs (p = 0. 5522) showed no significant variation. Overexpressing miR-34a-5p caused a decrease in the rate at which KGN cells multiplied and an increase in programmed cell death. Conversely, inhibiting miR-34a-5p resulted in an increase in cell growth and a decrease in programmed cell death. Bioinformatics analysis and experimental results further demonstrated thatmiR-34a-5p interacts with the 3'UTR region of JAG1, leading to a negative regulation of the Jagged1-Notch signaling pathway.

In summary, the miR-34a-5p molecule inhibits the growth of GCs as well as triggers programmed cell death by regulating the Jagged1-Notch signaling pathway. Silencing miR-34a-5p prevents dysfunction in GCs. Our analysis implies that miR-34a-5p is a new molecular site to treat PCOS.

Cell death is critical in tumor biology. The common cancer therapies can cause cell death and alleviate tumor, while the cancer cells can develop a resistance to cell death and survive from the therapies. Thus, not only observing the alternative mechanisms of tumor cells resistant to cell death, but also understanding the intricate dynamics of cell death processes within the tumor microenvironment (TME), are essential for tailoring effective therapeutic strategies. High-throughput sequencing technologies have revolutionized cancer research by enabling comprehensive molecular profiling. Recent advances in single cell sequencing have unraveled the heterogeneity of TME components, shedding light on their complex interactions. In this review, we explored the interplay between cell death signaling and the TME, summarised the potential drugs inducing cell death in pre-clinical stage, reviewed some studies applying next-generation sequencing technologies in cancer death research, and discussed the future utilization of updated sequencing platforms in screening novel treatment methods targeted cell death. In conclusion, leveraging multi-omics technologies to dissect cell death signaling in the context of the TME holds great promise for advancing cancer research and therapy development.

The BH3-interacting domain death agonist (Bid), a proapoptotic signaling molecule of the B-cell lymphoma 2 (Bcl-2) family, is a key regulator of mitochondrial outer membrane (MOM) permeability. Uniquely positioned at the intersection of extrinsic and intrinsic apoptosis pathways, Bid links death receptor signaling to the mitochondria-dependent cascade and can also be activated by endoplasmic reticulum (ER) stress. In its active forms, cleaved Bid (cBid) and truncated Bid (tBid), it disrupts MOM integrity via Bax/Bak-dependent and independent mechanisms. Apoptosis plays a dual role in viral infections, either promoting or counteracting viral propagation. Consequently, viruses modulate Bid signaling to favor their replication. The deregulation of Bid activity contributes to oncogenic transformation, inflammation, immunosuppression, neurotoxicity, and pathogen propagation during various viral infections. In this work, we explore Bid's structure, function, activation processes, and mitochondrial targeting. We describe its role in apoptosis induction and its involvement in infections with multiple viruses. Additionally, we discuss the therapeutic potential of Bid in antiviral strategies. Understanding Bid's signaling pathways offers valuable insights into host-virus interactions and the pathogenesis of infections. This knowledge may facilitate the development of novel therapeutic approaches to combat virus-associated diseases effectively.

Previous studies indicate that MAF BZIP Transcription Factor F (MAFF) facilitates ectopic metastasis and tumor cell migration. While its role in neoplasm progression is recognized, a thorough pan-cancer analysis of MAFF's impact remains pending.

MAFF expression across normal and tumor tissues was analyzed using transcriptomic data from Genomic Data Commons (GDC) and UCSC XENA, with protein details from Human Protein Atlas (HPA) and GeneMANIA. Tumor Immune Single-cell Hub (TISCH) and Spatial Transcriptomics Omics DataBase (STOmics DB) identified MAFF expression in the tumor microenvironment (TME). MAFF's prognostic significance and immune-related gene associations were evaluated through univariate Cox regression, TIMER2.0 immune cell infiltration analysis, and Spearman correlation. Critical pathways were identified using Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), while molecular docking explored anticancer agent interactions.

MAFF expression varies across cancers, affecting tumor prognosis, notably in monocytes/macrophages and endothelial cells. Copy number variation (CNV) positively correlates with MAFF expression, while methylation shows inverse correlation. MAFF mutations significantly affect LGG patient prognosis and correlate with immune therapy responses. ESTIMATE and immune profiling linked MAFF to immunosuppression pathways. Molecular docking identified MAFF-targeted drugs, with validated effects on breast cancer and endometrial cancer cell survival and migration in vitro.

Multi-omics analysis identified MAFF as a potential prognostic marker correlating with tumor immunity and microenvironment, suggesting its value for personalized cancer immunotherapy, particularly in BRCA and UCEC.

Cell death is a fundamental process that needs to be maintained to balance cellular functions and prevent disease. There are several cell death pathways; however, apoptosis and parthanatos are the most prominent and have important roles in cancer biology. As an extremely well-regulated process, apoptosis removes damaged or abnormal cells via caspase activation and mitochondrial involvement. Unlike in the healthy cells, the loss of ability to induce apoptosis in cancer permits tumor cells to survive and multiply out of control and contribute to tumor progression and therapy resistance. On the contrary, parthanatos is a caspase-independent metabolic collapse driven by poly (ADP-ribose) polymerase 1 (PARP1) overactivation, translocation of apoptosis-inducing factor (AIF), and complete DNA damage. Several cancer models are involved with parthanatos. Deoxypodophyllotoxin (DPT) induces parthanatos in glioma cells by excessive ROS generation, PARP1 upregulation, and AIF nuclear translocation. Like in acute myeloid leukemia (AML), the cannabinoid derivative WIN-55 triggers parthanatos, and the effects can be reversed by PARP inhibitors such as olaparib. Developing cancer treatment strategies involving advanced cancer treatment strategies relies on the interplay between apoptosis and parthanatos. However, such apoptosis-based cancer therapies tend to develop resistance, so there is an urgent need to look into alternative pathways like parthanatos, which may not always trigger apoptosis. In overcoming apoptosis resistance, there is evidence that combining apoptosis-inducing agents, such as BH3 mimetics, with PARP inhibitors synergistically enhances cell death. Oxidative stress modulators have been found to promote the execution of parthanatic and apoptotic pathways and allow treatment. In this review, apoptosis and parthanatos are thoroughly compared at the molecular level, and their roles in cancer pathogenesis as related to cancer therapeutic potential are discussed. We incorporate recent findings to demonstrate that not only can parthanatos be used to manage therapy resistance and enhance cancer treatment via the combination of parthanatos and apoptosis but also that immunity and bone deposition can feasibly be employed against long-circulating cancer stem cells to treat diverse forms of metastatic cancers.

Artemisia species are characterised by their antioxidant, anticancer, antibacterial, and anti-diabetic activities thanks to their phenolic and flavonoid content. These phenolic and flavonoid chemicals scavenge free radicals and reduce oxidative stress, which helps to guard against many diseases brought on by the buildup of free radicals and increased oxidative stress. In addition to acting as an antibacterial agent, it assisted in preventing cancer, hyperglycaemia, and diabetes. Antioxidant research has generally drawn attention due to its major contribution to the fight against numerous chronic illnesses, such as cancer and cardiovascular disorders. Several techniques were used to measure the enzymatic antioxidants (glutathione reductase, catalase, peroxidase, ascorbate oxidase, guaiacol peroxidase, superoxide dismutase and ascorbate peroxidase) in addition to the nonenzymatic antioxidants such as total phenolic acids, total polyphenol, ascorbic acid, total flavonoids and anthocyanin. Artemisinin (endoperoxide 1,2,4-trioxane ring.) is the main therapeutic constituent of Artemisia species.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide and the most common form of liver cancer. Despite global efforts toward early diagnosis and effective treatments, HCC is often diagnosed at advanced stages, where conventional therapies frequently lead to resistance and/or high recurrence rates. Therefore, novel biomarkers and promising medications are urgently required. Epi-drugs, or epigenetic-based medicines, have recently emerged as a promising therapeutic modality. Since the epigenome of the cancer cells is always dysregulated and this is followed by apoptosis-resistance, reprogramming the epigenome of cancer cells by epi-drugs (such as HDAC inhibitors (HDACis), and DNMT inhibitors (DNMTis)) could be an alternative approach to use in concert with established treatment protocols. C-FLIP, an anti-apoptotic protein, and Ku70, a member of the DNA repair system, bind together and make a cytoplasmic complex in certain cancers and induce resistance to apoptosis. Many epi-drugs, such as HDACis, can dissociate this complex through Ku70 acetylation and activate cellular apoptosis. The novel compounds for dissociating this complex could provide an innovative insight into molecular targeted HCC treatments. In this review, we address the innovative therapeutic potential of targeting c-FLIP/Ku70 complex by epi-drugs, particularly HDACis, to overcome apoptosis resistance of HCC cells. This review will cover the mechanisms by which the c-FLIP/Ku70 complex facilitates cancer cell survival, the impact of epigenetic alterations on the complex dissociation, and highlight HDACis potential in combination therapies, biomarker developments and mechanistic overviews. This review highlights c-FLIP ubiquitination and Ku70 acetylation levels as diagnostic and prognostic tools in HCC management.

Breast cancer is one of the most common cancers found in women worldwide. Besides the availability of clinical drugs, drug resistance and considerable side effects are concerning issues driven the needs for the discovery of novel anticancer agents. Aromatase inhibition is one of the effective strategies for management of hormone-dependent breast cancer. Triazole, coumarin, and isatin are heterocyclic scaffolds holding great attention in the field of drug design. Molecular hybridization is a well-known strategy to achieve new molecules with improved potency and properties. Herein, a set of 27 triazole-based hybrids (i.e., coumarin-triazoles series 5-6 and isatin-triazoles series 7) were synthesized and investigated for their anti-proliferation, apoptosis induction, and aromatase inhibitory potentials. Anti-proliferative study against the hormone-dependent breast cancer (T47D) cell line indicated that coumarin-triazoles 5h (R=NO2) and 6i (R=SO2NH2) were the two most potent antiproliferative agents. Particularly, compound 5h showed comparable potency and superior selectivity index than that of the reference drug, doxorubicin. Moreover, the coumarin-triazole 5h induced cellular apoptosis of the estrogen-dependent breast cancer (MCF-7) cells. Additionally, findings from the aromatase inhibitory assay suggested four compounds as potential aromatase inhibitors (i.e., 5i, 6f, 6g and 6i, IC50 = 1.4-2.4 μM). Two QSAR models with preferable predictive performances were constructed to reveal key properties influencing antiproliferative and aromatase inhibitory effects. Molecular docking was conducted to elucidate the possible binding modalities against the target aromatase enzyme. Key structural features essential for the binding were highlighted. Moreover, the drug-like properties of top-ranking compounds were assessed to ensure their possibilities for successful development.

Cholangiocarcinoma is a hepatobiliary system tumor with a high mortality rate. Although durvalumab and trastuzumab deruxtecan (T-DXd) have shown efficacy in treating cancers such as non-small cell lung cancer, their effects and regulatory mechanisms in cholangiocarcinoma remain unclear. In this study, we aimed to investigate the role and mechanism of durvalumab and T-DXd in inducing apoptosis in cholangiocarcinoma cells. Cholangiocarcinoma cells were treated with varying concentrations of durvalumab and T-DXd, either individually or in combination, to evaluate their effects. Apoptosis was quantified using flow cytometry. Quantitative real-time PCR (qPCR) and Western blotting were used to measure the mRNA expression and protein levels of genes associated with apoptosis and cell cycle regulation. The underlying mechanism was further explored through pathway enrichment analysis of differentially expressed genes (DEGs) and corroborated by qPCR and Western blotting. Xenotransplantation models using immune-deficient NOD-SCID/IL2Rγnull (NSG) mice were established to assess the in vivo effects of durvalumab and T-DXd. Our results showed that both durvalumab and T-DXd inhibited cholangiocarcinoma cell proliferation in a dose-dependent manner. Both agents promoted apoptosis and arrested the cell cycle of cholangiocarcinoma cells, with the combination treatment having the most significant effect. Furthermore, treatment with durvalumab, T-DXd, and the combination downregulated the protein levels of early growth response 1 (EGR1) by inactivating the p38 mitogen-activated protein kinase (MAPK) pathway. In vivo experiments indicated that durvalumab and T-DXd prolonged the survival of NSG mice bearing cholangiocarcinoma xenografts. In conclusion, our findings demonstrated that durvalumab and T-DXd synergistically promoted apoptosis in cholangiocarcinoma cells by inhibiting EGR1 expression through inactivation of the p38 MAPK pathway. This study confirmed the potential of durvalumab and T-DXd for the treatment of cholangiocarcinoma.

Recent reports have suggested an inverse relationship between Alzheimer's disease (AD) and cancer, although the underlying mechanism remains unclear. We performed an epidemiological meta-analysis to assess cancer likelihood in AD patients and vice versa and explored the role of APOE in tumor immunity across 33 The Cancer Genome Atlas (TCGA) cancer types. Our analysis revealed that people with AD are epidemiologically less likely to develop cancer than individuals without AD (RR: 0.53), and cancer patients are less likely to develop AD than non-cancer patients (RR: 0.61). Notably, APOE expression was positively associated with anti-tumor immune signatures and prevalent in early-stage tumors. This research reveals that AD patients are less likely to develop cancer and vice versa, pinpoints APOE gene as a risk factor for AD with anti-tumor activity, and provides new insight into the epidemiologically observed inverse relationship between both diseases.

This review discusses the literature data on the synthesis, physicochemical properties, and cytotoxicity of composite nanoparticles bearing the mitochondrial protein cytochrome c (cytC), which can act as a proapoptotic mediator in addition to its main function as an electron carrier in the electron transport chain. The introduction of exogenous cytC via absorption of carrier particles, the phagocytosis of colloid particles of submicrometric size, or the receptor-mediated endocytosis of nanoparticles in cancer cells, initiates the process of apoptosis-a multistage cascade of biochemical reactions leading to complete destruction of the cells. CytC-carrier composite particles have the potential for use in the treatment of neoplasms with superficial localization: skin, mouth, stomach, colon, etc. This approach can solve the two main problems of anticancer therapy: selectivity and non-toxicity. Selectivity is based on the incapability of the normal cell to absorb (nano)particles, except for the cells of the immune system. The use of cytC as a protein that normally functions in mitochondria is harmless for the macroorganism. In this review, the factors limiting cytotoxicity and the ways to increase it are discussed from the point of view of the physicochemical properties of the cytC-carrier particles. The different techniques used for the preparation of cytC-bearing colloids and nanoparticles are discussed. Articles reporting the achievement of high cytotoxicity with each of the techniques are critically analyzed.

Ovarian cancer is the most prevalent malignant tumor of the female reproductive system and has the highest mortality rate among gynecological cancers. Columbianetin acetate (CE) is one of the active ingredients of Angelica sinensis, which has good antifungal and anti-inflammatory activities. However, its potential mechanism of action in ovarian cancer remains unclear. This study used network pharmacology and molecular docking technology to investigate the molecular mechanism and material basis of CE in the treatment of ovarian cancer, and further verified by in vitro experiments.

Relevant targets for CE were obtained from TCMSP and SwissTargetPrediction databases. OMIM, GeneCards and DisGeNET databases were applied to screen ovarian cancer-related targets. The STRING database to obtain protein-protein interaction (PPI) network. Then key targets were obtained using Cytoscape software, followed by expression, survival and ROC diagnostic analyses of core genes using R software. GO and KEGG enrichment analyses were performed using the DAVID database. Binding ability of CE to core targets was assessed by molecular docking. KEGG sites were used to predict core gene-related pathways. Subsequently, in vitro cellular experiments were performed to further investigate the molecular mechanism of CE treatment for ovarian cancer.

A total of 55 CE-ovarian cancer interaction targets were identified using network pharmacology techniques. Among these, eight key targets -ESR1, GSK3B, JAK2, MAPK1, MDM2, PARP1, PIK3CA, and SRC-were screened using Cytoscape software. Core genes ESR1, GSK3B and JAK2 were obtained based on expression, prognostic and diagnostic values using R software. GO and KEGG enrichment analyses indicated that CE treatment of ovarian cancer might be related to PI3K/Akt signaling pathway, MAPK signaling pathway, ErbB signaling pathway and Ras signaling pathway. The molecular docking results showed that CE had good binding ability with core targets ESR1, GSK3B and JAK2. The results of in vitro cellular experiments indicated that CE may inhibit the proliferation and metastasis of ovarian cancer and promote apoptosis by inhibiting the PI3K/AKT/GSK3B pathway.

Based on the network pharmacology approach, we predicted the potential mechanism of CE for the treatment of ovarian cancer, which provided a new idea for further research on its pharmacological mechanism.

Immunogenic cell death (ICD) has attracted enormous attention over the past decade due to its unique characteristics in cancer cell death and its role in activating innate and adaptive immune responses against tumours. Many efforts have been dedicated to screening, identifying and discovering ICD inducers, resulting in the validation of several based on metal complexes. In this review, we provide a comprehensive summary of current metal-based ICD inducers, their molecular mechanisms for triggering ICD initiation and subsequent protective antitumour immune responses, along with considerations for validating ICD both in vitro and in vivo. We also aim to offer insights into the future development of metal complexes with enhanced ICD-inducing properties and their applications in potentiating antitumour immunity.

Ovarian cancer is one of most common gynaecologic malignancy and ranks third in cancer-related deaths among women. Ursolic acid (UA) is a pharmacologically active pentacyclic triterpenoid isolated from a large variety of vegetables, fruits and many traditional medicinal plants. However, the mechanism of action of UA in inhibiting the proliferation of ovarian cancer cells remains unclear. Consequently, this experiment was designed to elucidate the mechanism of action of UA in inhibiting the proliferation of ovarian cancer cells in greater detail.The results indicated that UA was capable of effectively inhibiting the proliferation, migration, and colony formation of ovarian cancer cells.UA was observed to up-regulate Bcl-2-associated X protein(BAX)and cysteinyl aspartate specific proteinase 3 (Caspase3) expression and down-regulating B-cell lymphoma-2(Bcl-2) expression.Meanwhile, UA up-regulated Sequestosome 1(p62)expression and down-regulated coiled-coil, moesin-like BCL2-interacting protein(Becline1), microtubule-associated proteins light chain 3(LC3), Phosphoinositide 3-Kinase(PI3K), andProtein Kinase B( AKT) expression, thus effectively inhibiting autophagy in ovarian cancer cells.Furthermore, UA upregulated pancreatic ER kinase (PKR)-like ER kinase (PERK), eukaryotic translation initiation factor 2 A(eIF2α), and The C/EBP Homologous Protein(CHOP) expression.In addition UA upregulates PERK, eIF2α, and CHOP expression and effectively promotes endoplasmic reticulum stress(ERS).In conclusion, UA can inhibit ovarian cancer cell proliferation, migration, colony formation, and may inhibit tumor cell autophagy by promoting tumor cell ERS, and ultimately promote ovarian cancer cell apoptosis.

ROS (Reactive Oxygen Species) has a dual role in tumorigenesis. Some cancers have high ROS conditions, and others have low ROS. TNBC thrives on high ROS compared to other Breast Cancer subtypes. Several antioxidant enzymes catalyze the detoxification of reactive oxygen species and prevent free radicals from damaging DNA and accumulation of mutation. Curcumin, a polyphenol dietary supplement, acts as a potent antioxidant, is known to reduce inflammation, and has anticancer properties. Here, we aim to understand alterations in the transcriptome (miRNA and mRNA expression) induced by ST09 in breast cancer cell lines. We identified an antioxidant system that is upregulated in breast cancer cell lines. Among the antioxidant enzymes regulated by miRNA was GPX3. A novel miRNA-mRNA antioxidant axis, miR-197-5p/GPX3, was observed in the TNBC cell line. We further validated the regulation of GPX3 by miRNA using luciferase assay. GPX3 overexpression, knockdown, and activity assay indicated the anti-tumorigenic role of GPX3 in the TNBC cell line. Further, treatment of TNBC xenograft with ST09 showed tumor reduction in vivo. ST09 potentiates the effect of standard-of-care (SOC) drug Cisplatin in vivo. ST09 can be exploited as a single chemotherapeutic agent or in combination treatment modalities, reducing the dosage of potent drugs.

Background: Pancreatic cancer (PCa) is one of the most malignant diseases in the world. Different from ferroptosis and apoptosis, disulfidptosis is a novel type of cell death. The role of disulfidptosis in PCa remains uncovered. Methods: Disulfidptosis-related lncRNAs were identified based on TCGA-PAAD database. The disulfidptosis-related predict signature was constructed and verified by bioinformatic analysis. TCGA and GTEx database and Renji tissue microarray (TMA) were applied to determine TMEM105 and its clinical significance. F-actin and PI staining were performed to detect disulfidptosis of PCa cells. The biological function of TMEM105 was investigated by loss-of-function and gain-of-function assays. RNA pull-down and LC-MS/MS analysis were employed to detect TMEM105 interacted proteins. The tissue samples from PCa patients with PET-CT information were utilized to validate the TMEM105-β-catenin-c-MYC-GLUT1 pathway in clinical settings. Results: A disulfidptosis-related predict signature, which was comprised of six lncRNAs, was constructed and validated by bioinformatic analysis. TMEM105 was identified as disulfidptosis-related lncRNA whose high expression predicted a poor prognosis in PCa. Functional studies revealed that TMEM105 promoted the growth and mitigated the disulfidptosis in PCa. Mechanically, TMEM105 upregulated the expression of β-catenin by maintaining the protein stability through the proteosome pathway. The forced expressed β-catenin increased the expression of glycolysis-related transcription factor c-MYC, thus induced the transcription activity of GLUT1. Conclusion: These results revealed the growth acceleration and the disulfidptosis mitigation function of TMEM105 in PCa. Targeting the TMEM105-β-catenin-c-MYC-GLUT1 pathway could be a potent therapy for PCa patients.

Polycystic ovary syndrome (PCOS) is a common disorder that affects the female reproductive system, with an incidence of 8 % to 15 %. It is characterized by irregular menstruation, hyperandrogenemia, and polycystic abnormalities in the ovaries. Nevertheless, there is still much to learn about the molecular pathways underlying PCOS. Apoptosis is the process by which cells actively destroy themselves, and it is vital to an organism's ability to develop normally and maintain homeostasis. In recent years, a growing body of research has indicated a connection between the pathophysiology of PCOS and apoptosis. Therefore, it is critical to comprehend the relationship between PCOS and apoptosis in greater detail, identify the pathophysiological underpinnings of PCOS, and provide fresh perspectives and targets for its treatment. This review aims to summarize the relationship between PCOS and apoptosis, discuss how apoptosis affects normal ovarian function and how it becomes dysfunctional in the ovaries of PCOS patients, and investigate the signaling pathways associated with apoptosis in PCOS, including PI3K-Akt, TNF, NF-κB, and p53. Additionally, potential therapeutic approaches for PCOS treatment are provided by summarizing the role of apoptosis in PCOS therapy.

Cancer diseases are a serious health problem for society, and among them cervical and prostate cancer rank high in terms of mortality. One of the reasons is the phenomenon of drug resistance and side effects accompanying conventional chemo- and radiotherapy. This requires continuous development of alternative treatment methods and searching for new compounds with anti-cancer potential. An example is quinalizarin, which was tested for its anti-cancer potential. The MTT test showed cytotoxic activity of quinalizarin against Hela and DU145 cell lines. Morphological analysis showed nuclear changes typical of apoptosis, which was confirmed by the annexin V/PE test, activation of caspases 3/7 and inhibition of Bcl-2 protein expression. Increased permeability of mitochondrial membranes and ROS generation were demonstrated. Inhibition of cell migration, blocking in the G0/G1 phase, increased number of cells with damaged DNA and an increase in markers of mitotic catastrophe, i.e. micro- and multinucleation including the presence of abnormal mitotic figures were also observed. At the same time, increased autophagy was observed, and preincubation of cells with chloroquine inhibited this process, which contributed to the increased cytotoxicity of quinalizarin towards the tested cells. Quinalizarin has a multidirectional effect based on apoptosis and alternative types of cell death.

Cancer is a multifaceted disease characterised by uncontrolled cellular proliferation and metastasis, resulting in significant global mortality. Current therapeutic strategies, including surgery, chemotherapy, and radiation therapy, face challenges such as systemic toxicity and tumour resistance. Recent advancements have shifted towards targeted therapies that act selectively on molecular structures within cancer cells, reducing off-target effects. Mitochondria have emerged as pivotal targets in this approach, given their roles in metabolic reprogramming, retrograde signalling, and oxidative stress, all of which drive the malignant phenotype. Targeting mitochondria offers a promising strategy to address these mechanisms at their origin. Synthetic derivatives of natural compounds hold particular promise in mitochondrial-targeted therapies. Innovations in drug design, including the use of conjugates and nanotechnology, focus on optimizing these compounds for mitochondrial specificity. Such advancements enhance therapeutic efficacy while minimizing systemic toxicity, presenting a significant step forward in modern anticancer strategies.

The present study aims to understand the molecular mechanism underlying the therapeutic effect of cerium nanoparticles (CeNPs) in oncology. Cancer cells were treated with different concentrations of pure nanocerium of different sizes synthesized by laser ablation. Due to the not insignificant influence of surface defects and oxygen species on the ROS-modulating properties of cerium nanoparticles, the nanoparticles were not coated with surfactants or organic molecules during synthesis, which could potentially inhibit a number of pro-oxidative effects. Reactive oxygen species (ROS) production, expression of genes encoding redox-status proteins, selenoproteins and proteins regulating cell death and endoplasmic reticulum stress (ER-stress) were investigated as indicators of the molecular mechanism of cancer cell death. Studies were conducted on the effects of cerium nanoparticles on the Ca2+ signaling system of cancer cells of different origins. Mouse fibroblasts (L-929 cell line) were used as non-cancerous ("normal") cells for which a whole series of experiments were performed, and a comparative analysis of the effects of nanoceria. It was found that 75 nm-sized cerium nanoparticles did not affect the redox-status and ROS production of cancer cells. In fibroblast cells, however, this nanoparticle diameter led to a deterioration of the cellular redox status and ROS production in a wide range of nanoparticle concentrations. Larger nanoparticles (100 nm-sized and 160 nm-sized), on the other hand, showed a different effect on cancer cells of different origins. In mouse fibroblast L-929 cells, however, 100 nm-sized or 160 nm-sized CeNPs acted in a high concentration range to disrupt mitochondrial membrane potential and activate early apoptosis. High concentrations of CeNPs were required to increase ROS production, reduce redox-status and induce apoptosis in human A-172 glioblastoma cells compared to the hepatocellular carcinoma cell line HepG2 and the breast cancer cell line MCF-7. In the A-172 glioblastoma cells, ER-stress was also not activated and their Ca2+ signaling system was activated by a significantly higher concentration of CeNPs, which could also contribute to the formation of tolerance of this cancer cell line to nanoceria. The Ca2+ signaling system of mouse fibroblasts was found to be highly sensitive to activation by nanoceria and the cells produced Ca2+ signals with higher amplitude compared to A-172 and MCF-7 cells.

BH3 mimetics are small‑molecule inhibitors of the antiapoptotic Bcl‑2 family and have therapeutic efficacy against hematological malignancies. BH3 mimetic A‑1331852 suppresses colorectal cancer cell proliferation. Progressive resistance to the widely used anticancer agent fluorouracil (5‑FU) is a key reason for colorectal cancer recurrence; therefore, the present study tested if A‑1331852 can suppress the proliferation of 5‑FU‑resistant colorectal cancer cells. A 5‑FU‑resistant colorectal cancer cell line was derived from HCT116 cells and compared with the parental line. Expression levels of the antiapoptotic Bcl‑2 proteins Bcl‑xL and myeloid cell leukemia 1 (Mcl‑1) were determined via western blotting, proliferation in the presence of 5‑FU and following small interfering (si)RNA‑mediated Bcl‑xL or Mcl‑1 knockdown was assessed by WST‑1 assay and sensitivity to A‑1331852‑induced apoptosis was assessed via western blotting and DNA fragmentation assay. In addition, a xenograft mouse model of 5‑FU‑resistant colorectal cancer was established via subcutaneous inoculation of 5‑FU‑resistant HCT116 cells to examine the in vivo antitumor efficacy of A‑1331852. Compared with the parental line, 5‑FU‑resistant cells overexpressed Bcl‑xL. Knockdown of Bcl‑xL by siRNA and treatment with A‑1331852 suppressed proliferation and induced the apoptosis of both 5‑FU‑resistant and parental HCT116 cells, but the potency of both effects was stronger in 5‑FU‑resistant than parental HCT116 cells. Furthermore, A‑1331852 suppressed the growth of xenograft tumors derived from 5‑FU‑resistant cells by inducing apoptosis. Overall, the present findings suggested that Bcl‑xL upregulation contributes to 5‑FU resistance of colorectal cancer and targeted inhibition by A‑1331852 may be an effective treatment strategy.

Gynecological tumors, such as ovarian, endometrial, and cervical cancers, alongside breast cancer, represent significant malignancies that pose serious threats to women's health worldwide. Standard treatments, including surgery, chemotherapy, radiotherapy, and targeted therapies, are commonly utilized in clinical practice. However, challenges such as high recurrence rates, drug resistance, and adverse side effects underscore the urgent need for more effective therapeutic options. Osthole, a natural coumarin compound derived from Chinese herbal medicine, has demonstrated remarkable antitumor activity against various cancers. Emerging evidence indicates that osthole can inhibit the proliferation, invasion, and metastasis of gynecological and breast cancer cells through various mechanisms, including inducing apoptosis and autophagy, regulating the tumor microenvironment, inhibiting tumor angiogenesis, and enhancing the sensitivity of cancer cells to chemotherapy and radiotherapy. This review highlights the recent advancements in osthole research within the context of gynecological and breast cancers, focusing on its molecular mechanisms, and offers a theoretical foundation for its potential development as an anticancer agent.

The roots of Rubia spp. (Rubiaceae) have been employed to treat hematemesis, inflammatory disease, and tumor. Cyclohexapeptides derived from Rubia spp. have been reported to have antitumor potential; however, the mechanism of action for their antitumor activity remains unclear. We aimed to examine the antitumor effect of deoxybouvardin glucoside (DBG), a cyclohexapeptide from Rubia spp. on oxaliplatin (Ox)-resistant human HCT116 colorectal cancer (CRC) cells. Cell viability in the presence of DBG was monitored using an MTT viability assay, and flow cytometry was used to analyze changes in apoptosis, cell cycle, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) activity. The antiproliferative activity involved apoptosis and phosphorylation of JNK and p38 MAPK. Inhibition of JNK and p38 MAPK by specific inhibitors prevented DBG-induced apoptosis, underscoring the close involvement of these kinases. Further, DBG induced cell cycle arrest in CRC cells at the G2/M phase by regulating the p21, p27, cyclin B1, and cdc2 proteins. DBG-induced apoptosis was accompanied mitochondrial membrane depolarization, resulting in cytochrome c release into the cytoplasm and caspase activation. Remarkably, DBG induced apoptosis by generating high ROS levels. The mediation of apoptosis by increased ROS generation was confirmed by pretreatment with the ROS scavenger N-acetyl cysteine (NAC). Collectively, DBG exhibited anticancer activity against both Ox-sensitive and Ox-resistant CRC cells by targeting JNK and p38 MAPK, inducing cell cycle arrest, elevating cellular ROS levels, and disrupting MMP. This study suggests that DBG has the potential to be utilized as a therapeutic agent for treating Ox-resistant CRC.