Search Results (3,397)

Triple-negative breast cancer (TNBC) is a highly aggressive and therapeutically challenging subtype of breast cancer due to its lack of estrogen receptors, progesterone receptors, and HER2 (Human epidermal growth factor receptor 2) expression, which severely limits available treatment options. Recently, Simvastatin—a widely used HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor for hyperlipidemia—has garnered interest for its potential anticancer effects. This study investigates the therapeutic potential of Simvastatin in triple-negative breast cancer (TNBC). The results demonstrate that Simvastatin significantly inhibits the proliferation of TNBC cells, particularly MDA-MB-231, in a dose- and time-dependent manner. Mechanistically, Simvastatin primarily induces G1 phase cell cycle arrest to exert its antiproliferative effects, with no significant evidence of apoptosis or necrosis. These findings support the potential repositioning of Simvastatin as a therapeutic agent to suppress TNBC cell growth. Further analysis shows that Simvastatin downregulates cyclin-dependent kinase 4 (CDK4), a key regulator of the G1/S cell cycle transition and a known marker of poor prognosis in breast cancer. These findings highlight a novel, apoptosis-independent mechanism of Simvastatin’s anticancer action in TNBC. Importantly, given that many breast cancer patients also suffer from hyperlipidemia, Simvastatin offers dual therapeutic benefits—managing both lipid metabolism and tumor cell proliferation. Thus, Simvastatin holds promise as an adjunctive therapy in the treatment of TNBC and warrants further clinical investigation. Full article

Background/Objectives: This study evaluated the in vitro probiotic potential of Lactiplantibacillus plantarum Probio87 (Probio87), focusing on its physiological robustness, safety, antimicrobial properties, and anticancer activity, with relevance to vaginal and cervical health. Methods: Tests included acid and bile salt tolerance, mucin adhesion, and carbohydrate utilization. Prebiotic preferences were assessed using FOS, GOS, and inulin. Antibiotic susceptibility was evaluated per EFSA standards. Antimicrobial activity of the cell-free supernatant (CFS) was tested against Staphylococcus aureus, Escherichia coli, and Candida species. Effects on Lactobacillus iners and L. crispatus were analyzed. Anticancer properties were assessed in HeLa, CaSki (HPV-positive), and C-33A (HPV-negative) cervical cancer cell lines through proliferation, apoptosis, angiogenesis, and cell cycle assays. Results: Probio87 showed strong acid and bile tolerance, efficient mucin adhesion, and broad carbohydrate utilization, favoring short-chain prebiotics like FOS and GOS over inulin. It met EFSA antibiotic safety standards. The CFS exhibited potent antimicrobial activity, including complete inhibition of Candida albicans. Probio87 selectively inhibited L. iners without affecting L. crispatus, indicating positive modulation of vaginal microbiota. In cervical cancer cells, the CFS significantly reduced proliferation and angiogenesis markers (p < 0.05), and induced apoptosis and cell cycle arrest in HPV-positive cells, with minimal effects on HPV-negative C-33A cells. Conclusions: Probio87 demonstrates strong probiotic potential, with safe, selective antimicrobial and anticancer effects. Its ability to modulate key microbial and cancer-related pathways supports its application in functional foods or therapeutic strategies for vaginal and cervical health. Full article

Virgin coconut oil (VCO) has emerged as a functional food oil with considerable health benefits and wide applications in the food, pharmaceutical, and cosmetic industries due to its resident bioactive compounds, including lauric acid (LA). LA is the most abundant saturated medium-chain fatty acid in VCO and has been associated with several pharmacological activities. The literatures show the pharmacological effects of VCO and LA on chronic pathologies, infectious diseases, and metabolic disorders. A robust body of evidence shows that LA and other phenolic compounds are responsible for the VCO protection against toxicities and pharmacological efficacies. This review elucidates the anticancer mechanisms of VCO/LA and their modulation of the chemotherapy-induced side effect toxicity. VCO, LA, and their nanomaterial/encapsulated derivatives promote ROS generation, antiproliferation, apoptosis, cell cycle arrest, the inhibition of metastasis, and the modulation of cancer-related signaling pathways for cancer cell death in vivo and in vitro. VCO mitigates oxidative inflammation and apoptosis to block the underlying mechanisms of the side effect toxicity of chemotherapy. However, the possible beneficial effect of LA on the toxicity of chemotherapy is currently unknown. The available evidence emphasizes the anticancer effect and mechanism of VCO and LA, and the VCO potential to combat adverse side effects of chemotherapy. Thus, VCO and LA are potential adjuvant therapeutic agents in the management of various cancers. Nevertheless, future studies should be targeted at elucidating cancer-related molecular mechanisms to bridge the gap in knowledge. Full article

CNOT2, a central component of the CCR4-NOT transcription complex subunit 2, plays a pivotal role in the regulation of gene expression and metabolism. CNOT2 is involved in various cellular processes, including transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability. CNOT2 specifically contributes to the structural integrity and enzymatic activity of the CCR4-NOT complex with transcription factors and RNA-binding proteins. Recent studies have elucidated its involvement in cellular differentiation, immune response modulation, and the maintenance of genomic stability. Abnormal regulation of CNOT2 has been implicated in a spectrum of pathological conditions, including oncogenesis, neurodegenerative disorders, and metabolic dysfunctions. This review comprehensively examines the interplay between CNOT2 and p53, elucidating their collaborative and antagonistic interactions in various cellular contexts. CNOT2 is primarily involved in transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability, thereby influencing diverse biological processes such as cell proliferation, apoptosis, and differentiation. Conversely, p53 is renowned for its role in maintaining genomic integrity, inducing cell cycle arrest, apoptosis, and senescence in response to cellular stress and DNA damage. Emerging evidence suggests that CNOT2 can modulate p53 activity through multiple mechanisms, including the regulation of p53 mRNA stability and the modulation of p53 target gene expression. The dysregulation of CNOT2 and p53 interactions has been implicated in the pathogenesis and progression of various cancers, highlighting their potential as therapeutic targets. Additionally, CNOT2 regulates c-Myc, a well-known oncogene, in cancer cells. This review shows the essential roles of CNOT2 in maintaining cancer cellular homeostasis and explores its interactions within the CCR4-NOT complex that influence transcriptional and post-transcriptional regulation. Furthermore, we investigate the potential of CNOT2 as a biomarker and therapeutic target across various disease states, highlighting its significance in disease progression and treatment responsiveness. Full article

The incidence and mortality of colorectal cancer (CRC) have increased globally. Several therapeutic approaches have been suggested to address this health issue, in addition to classical methods. Propranolol (PRO) is a beta-blocker that was repurposed to treat infantile hemangiomas, and its anti-tumor activity has been reported. This study aimed to investigate the effects of PRO in a panel of CRC cell lines and its potential impact when combined with chemotherapy. The effects of PRO on cell cytotoxicity, cell morphology, colony formation, cell death induction, cell cycle, mitochondrial and intracellular reactive oxygen species (ROS), and migration were measured in all cells. CompuSyn software was utilized to assess the possible synergistic or additive interaction in the combined treatment. The results showed that PRO suppressed cell proliferation, altered cell morphology, inhibited colony formation, induced apoptosis, altered cell cycle and ROS generation, and inhibited the migration of treated cells in a cell-type-specific, time-dependent, and dose-dependent manner compared with the control. HT-29 was the most sensitive cell line to PRO in terms of cytotoxicity, apoptosis, cell cycle arrest, and ROS generation, while SW-480 was the most sensitive in terms of migration inhibition. Moreover, the PRO and capecitabine combination exhibited a synergistic effect and induced mitochondrial apoptosis in metastatic CRC cells. The data suggest that PRO could be a promising adjuvant therapy for primary and advanced CRC. This study identified variations between CRC cell lines in response to PRO, which may be related to their genetic and epigenetic differences. In addition, the findings highlight the potential of combination strategies to improve therapeutic outcomes in metastatic CRC. Full article

Background: Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Full article

Background/Objectives: Cancer suffers from unresolved therapeutic challenges owing to the lack of targeted therapies and heightened recurrence risk. This study aimed to investigate the new series of hydroxamate by structurally modifying the pharmacophore of vorinostat. Methods: The present work involves the synthesis of 15 differently substituted 2H-1,2,3-triazole-based hydroxamide analogs by employing triazole ring as a cap with varied linker fragments. The compounds were evaluated for their anticancer effect, especially their anti-breast cancer response. Molecular docking and molecular dynamics simulations were conducted to examine binding interactions. Results: Results indicated that among all synthesized hybrids, the molecule VI(i) inhibits the growth of MCF-7 and A-549 cells (GI₅₀ < 10 μg/mL) in an antiproliferative assay. Compound VI(i) was also tested for cytotoxic activity by employing an MTT assay against A549, MCF-7, and MDA-MB-231 cell lines, and the findings indicate its potent anticancer response, especially against MCF-7 cells with IC₅₀ of 60 µg/mL. However, it experiences minimal toxicity towards the normal cell line (HEK-293). Mechanistic studies revealed a dual-pathway activation: first, apoptosis (17.18% of early and 10.22% of late apoptotic cells by annexin V/PI analysis); second, cell cycle arrest at the S and G2/M phases. It also promotes ROS generation in a concentration-dependent manner. The HDAC–inhibitory assay, extended in silico molecular docking, and MD simulation experiments further validated its significant binding affinity towards HDAC 1 and 6 isoforms. DFT and ADMET screening further support the biological proclivity of the title compounds. The notable biological contribution of VI(i) highlights it as a potential candidate, especially against breast cancer cells. Full article

Acute myeloid leukemia (AML) is a malignant hematological tumor with a high prevalence in elderly people, and circular RNA (circRNA) plays an important role in age-related diseases. Induction of cancer cell senescence is a highly promising therapeutic strategy; however, the presence of senescence-associated circRNAs in AML remains to be elucidated. Here, we show that the expression patterns of circRNAs differed between elderly AML patients and healthy volunteers. circSATB1 was significantly overexpressed in elderly patients and AML cells. Knockdown of circSATB1 resulted in the inhibition of proliferation and arrest of the cell cycle in the G0/G1 phase; no effect on apoptosis or DNA integrity was observed, and precocious cellular senescence was promoted, characterized by no change in telomere length. Database analysis revealed that there may be two miRNA and nine RNA-binding proteins (RBPs) involved in regulating the cellular functions of circSATB1. Our observations uncover circSATB1-orchestrated cell senescence in AML, which provides clues for finding more modest therapeutic targets for AML. Full article

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial–mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022–2024) and highlights isorhamnetin’s roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin’s delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies. Full article

To explore the potential seed compounds from natural products as anticancer agents against small-cell lung cancer (SCLC), the underground parts of Agapanthus africanus, a plant commonly used for ornamental purposes, were investigated. Three spirostan-type steroidal glycosides (1–3) were isolated and identified by nuclear magnetic resonance spectral analysis. Compounds 1–3 exhibited cytotoxicity against SBC-3 human SCLC cells, with IC₅₀ values of 0.56, 1.4, and 7.4 µM, respectively. Compound 1, also known an agapanthussaponin A, demonstrated the most potent cytotoxicity among the isolated compounds and was evaluated for its apoptosis- and ferroptosis-inducing activities. Compound 1 arrested the cell cycle of SBC-3 cells in the G₂/M phase and induced apoptosis primarily via the mitochondrial pathway, characterized by caspases-3 and -9 activation, loss of mitochondrial membrane potential, and overproduction of reactive oxygen species. Additionally, 1 triggered ferroptosis via a dual mechanism consisting of enhanced cellular iron uptake through upregulation of transferrin and transferrin receptor 1 expression and impaired glutathione synthesis via downregulation of both xCT and glutathione peroxidase 4 expression. Compound 1 induces cell death via the apoptosis and ferroptosis pathways, suggesting its promise as a seed compound for the development of anticancer therapeutics against SCLC. Full article

Hodgkin lymphoma (HL) is a common neoplasm in adolescents and young adults, primarily treated with doxorubicin (DOX) and bleomycin (BLM), which may cause severe adverse effects. The cure rate decreases to 75% in advanced-stage disease, highlighting the need for improved treatment strategies. Pentoxifylline (PTX), an NF-κB pathway inhibitor, enhances chemotherapy-induced apoptosis in cancer cells, making it a promising candidate for HL therapy. This study assessed the effects of PTX, DOX, and BLM on apoptosis, proliferation, and senescence in Hs-445 HL cells. Cell viability and clonogenicity were measured by spectrophotometry and spectrofluorimetry, while apoptosis, caspase activity, cell cycle, mitochondrial membrane potential (ΔΨm), proliferation, and senescence were analyzed via flow cytometry. Gene expression was assessed by qPCR. PTX significantly induced apoptosis, especially when combined with BLM or BLM+DOX (triple therapy), and modulated gene expression by upregulating proapoptotic and downregulating antiapoptotic markers. PTX increased caspase-3, -8, and -9 activity and disrupted the ΔΨm, particularly with BLM or triple therapy. Furthermore, PTX abolished DOX-induced G2 cell cycle arrest, reduced proliferation, and clonogenicity, and reversed DOX- and BLM-induced senescence. In conclusion, PTX induces apoptosis in HL cells, enhances DOX and BLM cytotoxicity synergistically, and reverses senescence, suggesting its potential as an adjunct therapy for HL. Full article

The protein p53, often referred to as the “guardian of the genome,” is essential for preserving cellular balance and preventing cancerous transformations. As one of the most commonly altered genes in human cancers, its impaired function is associated with tumor initiation, development, and resistance to treatment. Exploring the diverse roles of p53, which include regulating the cell cycle, repairing DNA, inducing apoptosis, reprogramming metabolism, and modulating immunity, provides valuable insights into cancer mechanisms and potential treatments. This review integrates recent findings on p53′s dual nature, functioning as both a tumor suppressor and an oncogenic promoter, depending on the context. Wild-type p53 suppresses tumors by inducing cell cycle arrest or apoptosis in response to genotoxic stress, while mutated variants often lose these functions or gain novel pro-oncogenic activities. Emerging evidence highlights p53′s involvement in non-canonical pathways, such as regulating tumor microenvironment interactions, metabolic flexibility, and immune evasion mechanisms. For instance, p53 modulates immune checkpoint expression and influences the efficacy of immunotherapies, including PD-1/PD-L1 blockade. Furthermore, advancements in precision diagnostics, such as liquid biopsy-based detection of p53 mutations and AI-driven bioinformatics tools, enable early cancer identification and stratification of patients likely to benefit from targeted therapies. Therapeutic strategies targeting p53 pathways are rapidly evolving. Small molecules restoring wild-type p53 activity or disrupting mutant p53 interactions, such as APR-246 and MDM2 inhibitors, show promise in clinical trials. Combination approaches integrating gene editing with synthetic lethal strategies aim to exploit p53-dependent vulnerabilities. Additionally, leveraging p53′s immunomodulatory effects through vaccine development or adjuvants may enhance immunotherapy responses. In conclusion, deciphering p53′s complex biology underscores its unparalleled potential as a biomarker and therapeutic target. Integrating multi-omics analyses, functional genomic screens, and real-world clinical data will accelerate the translation of p53-focused research into precision oncology breakthroughs, ultimately improving patient outcomes. Full article

The increasing prevalence of cancer necessitates the development of novel and effective therapeutic agents. This study evaluates the anticancer potential of biosynthesized copper oxide nanoparticles (CuO NPs) using Camellia sinensis extract against human colon and breast cancer cells. The CuO NPs were characterized using various techniques to confirm their structure, size, morphology, and functional groups. The average size of CuO NPs synthesized was 20–60 nm, with spherical shape. The cytotoxic effects of these CuO NPs reveal a dose-dependent reduction in cell viability with 50% inhibitory concentration (IC₅₀) at 58.53 ± 0.13 and 53.95 ± 1.1 μg/mL, respectively. Further investigation into the mechanism of action was conducted using flow cytometry and apoptosis assays, which indicated that CuO NPs induced cell cycle arrest and apoptosis in cancer cells. Reactive oxygen species (ROS) generation, caspase activity assay, and comet assay were also performed to elucidate the underlying pathways, suggesting that oxidative stress and DNA damage play pivotal roles in the cytotoxicity observed. Overall, our findings demonstrate that biosynthesized CuO NPs exhibit notable anticancer activity against colon and breast cancer cells, with moderate selectivity over normal cells, highlighting their potential as a therapeutic agent due to their biocompatibility. However, further studies are required to validate their selectivity and safety profile. Full article

Lymphoma is the most common neoplasm of lymphoid tissues in dogs. Exportin 1 (XPO1) is an important major nuclear receptor for exporting proteins and RNA species. The XPO1 upregulation can eliminate some tumor suppressor proteins (TSPs) function upon their nuclear–cytoplasmic export. The XPO1 inhibitor, KPT-335, blocks the translocation of TSPs and restores their function to induce cell cycle arrest, apoptosis, and cell proliferation. This in vitro study aimed to evaluate the XPO1 mRNA and protein expression in canine lymphoma cell lines and confirm the relevance with KPT-335. XPO1 mRNA and protein levels were quantified, and the effect of KPT-335 was assessed by a cell proliferation assay. The results indicated that XPO1 mRNA and protein were highly expressed in 17-71, CLBL-1, CLC, CLGL-90, and UL-1, and were moderately expressed in GL-1, Ema, and Nody-1. All canine lymphoma cell lines showed dose-dependent growth inhibition and decreased cell viability in response to KPT-335, with IC₅₀ concentrations ranged from 89.8–418 nM. The expression levels of XPO1 mRNA and protein were related; however, no correlation was found between those expression levels and the efficacy of KPT-335. These findings suggest that XPO1 may represent a promising target for therapeutic intervention in canine lymphoma. Full article

Flammulina velutipes is a widely cultivated edible mushroom in East Asia, recognized for its nutritional benefits and distinct morphology characterized by a long stipe and a compact, hemispherical pileus. The pileus not only plays a critical biological role in reproduction through spore formation but also serves as a key commercial trait influencing consumer preference and market value. Despite its economic importance, pileus development in F. velutipes is highly sensitive to environmental factors, among which carbon dioxide (CO₂) concentration is particularly influential under indoor cultivation conditions. While previous studies have reported that elevated CO₂ levels can inhibit pileus expansion in other mushroom species, the molecular mechanisms by which CO₂ affects pileus growth in F. velutipes remain poorly understood. In this study, we investigated the impact of CO₂ concentration on pileus morphology and gene expression in F. velutipes by cultivating fruiting bodies under two controlled atmospheric conditions: low (1000 ppm) and high (10,000 ppm) CO₂. Morphometric analysis revealed that elevated CO₂ levels significantly suppressed pileus expansion, reducing the average diameter by more than 50% compared to the low CO₂ condition. To elucidate the underlying genetic response, we conducted RNA sequencing and identified 102 differentially expressed genes (DEGs), with 78 being downregulated under elevated CO₂. Functional enrichment analysis highlighted the involvement of cyclin-dependent protein kinase regulatory pathways in this response. Two cyclin genes were found to be significantly downregulated under elevated CO₂ conditions, and their suppression was validated through quantitative real-time PCR. These genes, possessing conserved cyclin_N domains, are implicated in the regulation of the eukaryotic cell cycle, particularly in mitotic growth. These results indicate that CO₂-induced downregulation of cyclin genes may underlie cell cycle arrest, contributing to inhibited pileus development. This study is the first to provide transcriptomic evidence that elevated CO₂ concentrations specifically repress PHO80-like cyclin genes in F. velutipes, revealing a molecular mechanism by which CO₂ stress inhibits pileus development. These findings suggest that elevated CO₂ triggers a morphogenetic checkpoint by repressing PHO80-like cyclins, thereby modulating cell cycle progression during fruiting body development. This study provides the first evidence of such a transcriptional response in edible mushrooms and offers promising molecular targets for breeding CO₂-resilient strains and optimizing commercial cultivation conditions. Full article