Search Results (503)

Breast cancer (BC) progression appears to be significantly influenced by the diabetic microenvironment, characterised by hyperglycaemia and hyperinsulinemia, though the exact cellular mechanisms remain partly unclear. This study investigated the effects of exposure to supra-physiological levels of glucose and insulin on two distinct BC cell models: hormone-responsive MCF-7 cells and triple-negative MDA-MB-231 cells. To evaluate the effects triggered by high insulin level in different BC cell subtypes, we analysed the activation status of PI3K/AKT and MAPK pathways, cell proliferation, cell distribution in cell cycle phases and cell migration. High insulin level significantly activates the insulin metabolic pathway via AKT phosphorylation in both cell lines while inducing pro-proliferative stimulus and modulation of cell distribution in cell cycle phases only in the hormone-responsive MCF-7 cell line. On the contrary, high-glucose containing medium alone did not modulate proliferation nor further increased it when combined with high insulin level in both the investigated cell lines. However, following insulin treatment, the MAPK pathway remained unaffected, suggesting that the proliferation effects in the MCF-7 cell line are mediated by AKT activation. This linkage was also demonstrated by AKT phosphorylation blockade, driven by the AKT inhibitor MK-2206, which negated the proliferative stimulus. Interestingly, while MDA-MB-231 cells, following chronic hyperinsulinemia exposure, did not exhibit enhanced proliferation, they displayed a marked increase in migratory behaviour. These findings suggest that chronic hyperinsulinemia, but not hyperglycaemia, exerts subtype-specific effects in BC, highlighting the potential of targeting insulin pathways for therapeutic intervention. Full article

Background/Objectives. This manuscript presents an overview of advances in oncological radiotherapy as an effective treatment method for cancerous tumors, focusing on mechanisms of action within metabolite–antimetabolite systems. The urgency of this topic is underscored by the fact that cancer remains one of the leading causes of death worldwide: as of 2022, approximately 20 million new cases were diagnosed globally, accounting for about 0.25% of the total population. Given prognostic models predicting a steady increase in cancer incidence to 35 million cases by 2050, there is an urgent need for the latest developments in physics, chemistry, molecular biology, pharmacy, and strict adherence to oncological vigilance. The purpose of this work is to demonstrate the relationship between the nature and mechanisms of past diagnostic and therapeutic oncology approaches, their current improvements, and future prospects. Particular emphasis is placed on isotope technologies in the production of therapeutic nuclides, focusing on the mechanisms of formation of simple and complex theranostic compounds and their classification according to target specificity. Methods. The methodology involved searching, selecting, and analyzing information from PubMed, Scopus, and Web of Science databases, as well as from available official online sources over the past 20 years. The search was structured around the structure–mechanism–effect relationship of active pharmaceutical ingredients (APIs). The manuscript, including graphic materials, was prepared using a narrative synthesis method. Results. The results present a sequential analysis of materials related to isotope technology, particularly nucleus stability and instability. An explanation of theranostic principles enabled a detailed description of the action mechanisms of radiopharmaceuticals on various receptors within the metabolite–antimetabolite system using specific drug models. Attention is also given to radioactive nanotheranostics, exemplified by the mechanisms of action of radioactive nanoparticles such as Tc-99m, AuNPs, wwAgNPs, FeNPs, and others. Conclusions. Radiotheranostics, which combines the diagnostic properties of unstable nuclei with therapeutic effects, serves as an effective adjunctive and/or independent method for treating cancer patients. Despite the emergence of resistance to both chemotherapy and radiotherapy, existing nuclide resources provide protection against subsequent tumor metastasis. However, given the unfavorable cancer incidence prognosis over the next 25 years, the development of “preventive” drugs is recommended. Progress in this area will be facilitated by modern medical knowledge and a deeper understanding of ligand–receptor interactions to trigger apoptosis in rapidly proliferating cells. Full article

Viral oncolysis is considered a promising cancer treatment method because of its good tolerability and durable anti-tumor effects. Compared with other oncolytic viruses, Newcastle disease virus (NDV) has some distinct advantages. As an RNA virus, NDV does not recombine with the host genome, making it safer compared with DNA viruses and retroviruses; NDV can induce syncytium formation, allowing the virus to spread among cells without exposure to host neutralizing antibodies; and its genome adheres to the hexamer genetic code rule (genome length as a multiple of six nucleotides), ensuring accurate replication, low recombination rates, and high genetic stability. Although wild-type NDV has a killing effect on various tumor cells, its oncolytic effect and working mechanism are diverse, increasing the complexity of generating engineered oncolytic viruses with NDV. This study aims to employ whole-genome CRISPR-Cas9 knockout screening and RNA sequencing to identify putative key regulatory factors involved in the interaction between NDV and human colon cancer HCT116 cells and map their global interaction networks. The results suggests that NDV infection disrupts cellular homeostasis, thereby exerting oncolytic effects by inhibiting cell metabolism and proliferation. Meanwhile, the antiviral immune response triggered by NDV infection, along with the activation of anti-apoptotic signaling pathways, may be responsible for the limited oncolytic efficacy of NDV against HCT116 cells. These findings not only enhance our understanding of the oncolytic mechanism of NDV against colonic carcinoma but also provide potential strategies and targets for the development of NDV-based engineered oncolytic viruses. Full article

Background/Objectives: Truncating mutations in PALB2, a critical component of the BRCA1-PALB2-BRCA2 homologous recombination repair complex, are associated with increased risk and aggressiveness of breast cancer. The consequences of PALB2 truncation on the expression, localization, and functional dynamics of the scaffold protein IQGAP1 were investigated in this study based on two cases of truncated PALB2 human breast invasive ductal carcinoma (IDC), specifically, c.1240C>T (p.Arg414*) and c.2257C>T (p.Arg753*). Methods: Using confocal microscopy, we examined co-expression patterns of IQGAP1 with PALB2, PCNA, CK7, and β-tubulin in tumor tissues from both control cancer and PALB2-mutated cases. Results: In PALB2-truncated tumors, IQGAP1 exhibited enhanced peripheral and plasma membrane localization with elevated co-localization levels compared to controls, suggesting altered cytoskeletal organization. PALB2 truncation increased nuclear and cytoplasmic N-terminal PALB2 immunoreactivity, indicating the presence of truncated isoforms disrupting the homologous recombination repair system. Co-expression analyses with PCNA revealed an inverse expression pattern between IQGAP1 and proliferation markers, suggesting S-phase cell cycle-dependent heterogeneity. Furthermore, the loss of IQGAP1 dominance over CK7 and β-tubulin in mutant tumors, along with persistent intercellular spacing, implied a loss of cell–cell cohesion and the acquisition of invasive traits. Conclusions: These data support a model where PALB2 truncation triggers a reorganization of IQGAP1 that disrupts its canonical structural functions and facilitates tumor progression via enhanced motility and impaired cell–cell interaction. IQGAP1 thus serves as both a functional effector and potential biomarker in PALB2-mutated IDC, opening novel paths for diagnosis and targeted therapeutic intervention. Full article

DNA is inherently unstable and is susceptible to damage from both endogenous sources (such as reactive oxygen species) and exogenous factors (including UV, ionizing radiation, and chemicals). The accumulation of DNA damage manifests as genetic mutations, chromosomal instability, and the stalling of DNA replication and transcription processes. Accumulated DNA damage influences apoptosis and cell cycle checkpoints, serving as one of the key triggers for the manifestation of the senescent phenotype. Both aging and cancer are associated with the accumulation of mutations in somatic cells. Disruption of cell cycle control and uncontrolled proliferation are fundamental characteristics of any cancer cell, with the majority of anticancer drugs acting as inhibitors of cyclin-dependent kinases, thereby inducing a transition of cells into a senescent state. Consequently, disturbances in the dynamics and regulation of inflammatory responses, oxidative stress, cell proliferation, DNA damage repair, and epigenetic anomalies, along with the influence of retroviruses and transposons, lead to the accumulation of senescent cells within the human body, characterized by blocked replication and cell cycle, as well as a distinct secretory phenotype. The age-related or disease-associated accumulation of these senescent cells significantly alters the physiology of tissues and the organism as a whole. Many secondary metabolites of higher plants exhibit senolytic and senomorphic activities, although most of them are not fully characterized. In this review, we will explore the principal signaling pathways in mammalian cells that govern the cell cycle and cellular senescence, with a particular emphasis on how their dynamics, expression, and regulation have been modified through the application of senotherapeutic compounds. The second section of the review will identify key target genes for the metabolic engineering, primarily aimed at enhancing the accumulation of plant secondary metabolites with potential therapeutic benefits. Lastly, we will discuss the rationale for utilizing liver cells as a model system to investigate the effects of senolytic compounds on human physiology and health, as well as how senotherapeutic substances can be leveraged to improve gene therapy approaches based on CRISPR/Cas9 and prime-editing technologies. Full article

Fatty acid synthase (FASN) is frequently overexpressed in human breast cancer and has emerged as a potential therapeutic target. Resveratrol has been shown to inhibit FASN activity in vitro through both fast-reversible and slow-irreversible mechanisms. In this study, resveratrol reduced intracellular fatty acid levels by inhibiting FASN activity and downregulating its expression across various breast cancer subtypes, including SK-BR-3, MCF-7, and MDA-MB-231 cells. Knockdown of FASN via small interfering RNA (siRNA) further enhanced resveratrol-induced cytotoxicity. Resveratrol significantly suppressed cell viability and triggered apoptosis, as evidenced by increased cleavage of poly(ADP-ribose) polymerase (PARP) and disruption of Bcl-2 family protein balance. Furthermore, resveratrol inhibited key signaling pathways involved in cell proliferation and survival, notably FAK, AKT, and ERK1/2. FASN silencing by siRNA also modulated the activation states of these signaling proteins. Collectively, these findings support resveratrol as a promising anti-cancer candidate that induces apoptosis in diverse breast cancer subtypes via FASN inhibition. Full article

Pancreatic cancer is one of the most lethal malignancies, in part due to its profound metabolic adaptability, which underlies drug resistance and therapeutic failure. This study explores the metabolic rewiring associated with resistance to treatment using a systems metabolomics approach. Exposure to the redox-disrupting agent erastin revealed key metabolic vulnerabilities but failed to produce lasting growth suppression. Combinatorial treatments with methotrexate or alpelisib significantly impaired proliferation and triggered marked metabolic shifts. Systems-level analyses identified serine metabolism as a central adaptive pathway in resilient cells. Metabolic tracing and gene expression profiling showed increased de novo serine biosynthesis and uptake, supporting redox homeostasis, biosynthetic activity, and epigenetic regulation. Notably, cells that resumed growth after drug withdrawal exhibited transcriptional reprogramming involving serine-driven pathways, along with elevated expression of genes linked to survival, proliferation, and migration. These findings establish serine metabolism as a functional biomarker of metabolic plasticity and adaptive resilience in pancreatic cancer, suggesting that targeting this adaptive axis may enhance therapeutic efficacy. Full article

Background/Objectives: Drug resistance and severe side effects caused by gemcitabine (Gem) and cisplatin (CDDP) are common. This study aimed to investigate the combined effects of CU4c and Gem or CDDP on lung cancer cells in vitro and in nude mouse xenograft models. Methods: Antiproliferative activity and drug interaction were evaluated using MTT and Chou–Talalay methods, respectively. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. The expression levels of proteins were evaluated by Western blot analysis. The HDAC-inhibitory activity of CU4c was confirmed in vitro, in silico, and in A549 cells. Results: CU4c inhibited the proliferation of A549 cells in a dose- and time-dependent manner but had little effect on the growth of noncancerous Vero cells. CU4c synergistically enhanced the antiproliferative activities of CDDP (at 24 h) and Gem (at 48 and 72 h) against A549 cells. Combined CU4c and CDDP notably inhibited A549 proliferation by triggering cell cycle arrest at S and G2/M phases at 24 h with elevated levels of p21 and p53 proteins. Combined CU4c and Gem induced cell cycle arrest at both the S and G2/M phases at 48 h via upregulating the expression of the p21 protein. CU4c enhanced the apoptotic effects of CDDP and Gem by increasing the Bax/Bcl-2 ratio, pERK1/2, and Ac-H3 levels. Combined CU4c and Gem significantly reduced tumor growth while minimizing visceral organ damage in animal study. Conclusions: These results suggest that CU4c enhances the anticancer activity of CDDP and Gem and reduces the toxicity of Gem in animal studies. Full article

Cellular senescence is a complex physiological process in which cells permanently stop dividing and enter a stable state of cell-cycle arrest. This mechanism is typically triggered by various stressors, such as DNA damage, oxidative stress, telomere shortening, and oncogene activation. Senescent cells remain metabolically active and significantly influence their microenvironment through the senescence-associated secretory phenotype (SASP), which includes the secretion of inflammatory cytokines, growth factors, and proteases. While cellular senescence serves as a crucial tumor-suppressive mechanism by preventing the proliferation of damaged or potentially cancerous cells, it also plays a paradoxical role by promoting chronic inflammation, tissue dysfunction, and potentially oncogenesis. Therefore, understanding the regulation and impact of cellular senescence is vital for developing therapeutic interventions that leverage its benefits while minimizing adverse outcomes. In this review, we provide an overview of the current understanding of cellular senescence in cancer biology and discuss the emerging field of senescence-targeted therapies. We focus specifically on the role of senescence in head and neck cancers, examining the potential of induced senescence therapy to mitigate the progression of these tumors. This review aims to correlate the dual nature of senescence with innovative therapeutic strategies, highlighting its promise and challenges in improving treatment outcomes for HNC patients. Full article

Breast cancer (BC) remains a significant therapeutic challenge, necessitating novel agents with multi-target efficacy. Here, we demonstrate that triptophenolide (TRI), a bioactive compound from Tripterygium wilfordii, exerts potent anti-BC activity across hormone-responsive (MCF-7) and triple-negative (MDA-MB-231) subtypes. In vitro, TRI inhibited proliferation in a concentration-dependent manner, with IC₅₀ values decreasing from 180.3 μg/mL (24 h) to 127.2 μg/mL (48 h) in MCF-7 cells, and from 322.5 μg/mL to 262.1 μg/mL in MDA-MB-231 cells. TRI treatment induced G1-phase arrest in both breast cancer subtypes, increasing the G1 population by 22.27% in MCF-7 cells and 10.64% in MDA-MB-231 cells. Concurrently, TRI triggered apoptosis, elevating apoptotic rates from 3.36% to 9.78% in MCF-7 cells and from 7.01% to 17.02% in MDA-MB-231 cells. These effects were associated with the significant upregulation of pro-apoptotic proteins BAX, BAK1, BIM, and cytochrome c (CYCS). Notably, TRI suppressed migration by 61.5% (MCF-7) and 71.5% (MDA-MB-231). In vivo, TRI treatment inhibited MCF-7 xenograft growth and reduced tumor volume (1207.5 vs. 285 mm³) and weight (0.22 vs. 0.1 g), while extending the survival time of tumor-bearing mice from 14–20 days to 24 days. These results position TRI as a promising lead therapeutic candidate against diverse BC subtypes, with mechanistic versatility surpassing single-target agents. Full article

Murine double minute 2 (MDM2) is involved in various cancers and is an attractive target. The RING domain of MDM2 has been discussed as an alternative target to stabilize p53. Designing drugs to target the RING domain of MDM2 is an alternative approach to preventing MDM2-mediated deactivation of p53. In this study, we obtained a human VH single-domain antibody and revealed its regulatory effects and mechanisms. The RING domain of MDM2 was synthesized using a chemical synthesis method, and antibodies against the MDM2 RING domain were screened from a human VH single-domain antibody library and expressed intracellularly. A nuclear localization sequence was designed to ensure intrabody efficiency. The binding activity of the individually cloned antibodies was detected using ELISA. MTT and flow cytometry assays were used to detect the reactions related to intrabody in vitro. The combination and its influence on MDM2 were detected using immunoprecipitation assays, confocal microscopy, and Western blotting. The effects on apoptosis-related mitochondrial pathways downstream of p53 were examined using Western blotting. The influence on cell cycle distribution and cyclin-related proteins was detected using flow cytometry and Western blotting. A549 cell xenografts were constructed to assess the effect of intrabodies on growth in vivo. The molecular mechanisms of MDM2 and p53 were studied using Western blotting. Eight individual cloned antibodies were positive compared to the signals on the BSA-coated plates, especially intrabodies VH-HT3. In A549 and MCF-7 cell lines, VH-HT3 exhibited significant inhibitory effects on cell proliferation and apoptosis. VH-HT3 co-localized with MDM2 in the nucleus and cytoplasm. The specific combination of VH-HT3 triggered no significant effect on MDM2 activity for p53 degradation but upregulated the levels of factors downstream of p53, especially those in the mitochondrial apoptosis pathway. Moreover, VH-HT3 induced cell cycle arrest, and the expression of cyclin-related proteins was consistent with this observation. VH-HT3 also retarded the growth of A549 xenografts in vivo. Further tests suggested that VH-HT3 inhibited MDM2 function by increasing HIPK2 levels and activating p53 at the Ser46 site. VH-HT3, prepared from a human VH single-domain antibody library, inhibited p53 activity and produced a tumor-suppressive effect. The intrabody VH-HT3 is a candidate for the development of novel MDM2 inhibitors. Full article

Cervical cancer remains a major threat to women’s health, with advanced cases often exhibiting recurrence and metastasis due to cancer stem cells driving therapy resistance. This study evaluated fenbendazole (FBZ), a repurposed veterinary anthelmintic, for its antitumor activity dual targeting cervical cancer cells (CCCs) and cervical cancer stem cells (CCSCs). CD133⁺CD44⁺ CCSCs were isolated from HeLa and C-33 A cell lines via immunomagnetic sorting and validated for stemness. Cell proliferation, cell cycle and apoptosis, and protein expression were detected by MST assay, flow cytometry, and Western blot analysis, respectively. FBZ dose-dependently inhibited proliferation, induced G2/M arrest, and triggered apoptosis in both CCCs and CCSCs. Mechanistically, FBZ upregulated cyclin B1 and phosphorylation of cdc25C-Ser198, while downregulating Wee1, phosphorylation of CDK1, and phosphorylation of cdc25C-Ser216, collectively enforcing G2/M blockade. In vivo, FBZ (100 mg/kg) significantly suppressed tumor growth in xenograft models without weight loss, contrasting with cisplatin-induced toxicity. Survival analysis revealed 100% survival in FBZ-treated mice versus 40% in cisplatin and 0% in untreated controls. These findings demonstrate FBZ’s unique ability to simultaneously target bulk tumor cells and therapy-resistant CCSCs via cell cycle disruption, supported by its preclinical safety and efficacy, positioning it as a promising therapeutic candidate for cervical cancer. Full article

Salivary gland cancers (SGCs) pose a therapeutic challenge due to their aggressive nature and limited treatment options. Ion transporters, particularly the sodium/iodide symporter (SLC5A5), which transport iodine in the form of iodide anion (I⁻) into cells, have emerged as potential therapeutic targets in tumors of glandular origin. Our research indicates that SLC5A5 is expressed predominantly in ductal cells of human and murine SGC cells. We assessed the effects of potassium iodide (KI), a source of iodide ions. KI treatment reduced SGC cell proliferation and viability without impacting migration. KI increased ROS levels and triggered caspase-dependent apoptosis, as indicated by the upregulation of the pro-apoptotic protein BAX, downregulation of the anti-apoptotic protein Bcl-2, and induction of SGC cell shrinkage. KI did not affect NF-κB or TNF-α and SLC5A5 expression. Adding the antioxidant N-acetylcysteine reversed KI-induced growth inhibition, underscoring ROS-induced oxidative stress’s crucial role in growth inhibition. While KI administered in drinking water to mice increased epidermal growth factor (EGF) expression in non-malignant salivary gland tissues, KI decreased EGF receptor (EGFR) expression in malignant SGC cell cultures, where EGFR signaling is frequently dysregulated in SGCs but promoted AKT phosphorylation. Combining KI and anti-EGFR treatment did not yield synergistic anti-SGC cell effects. The study underscores the therapeutic potential of KI as a standalone treatment in vitro for SGC cells. However, the upregulation of EGF in non-malignant tissues and, therefore, the possibility to enhance EGFR-driven signals and AKT phosphorylation after KI treatment in cancer patients could indicate a risk of rendering SGC cells more drug resistant, warranting further investigation to optimize its clinical application. Full article

Background/Objectives: Ribosomal Protein Lateral Stalk Subunit P2 (RPLP2), an important ribosomal protein, is mainly involved in modulating protein synthesis and plays an essential role in the carcinogenesis of many cancers. However, its precise impact on diffuse large B-cell lymphoma (DLBCL) remains unknown. Methods: This study utilized siRNA to knock down RPLP2, aiming to investigate its role in DLBCL progression. RT-qPCR and immunohistochemistry (IHC) were employed to assess RPLP2 and frataxin (FXN) expression levels in DLBCL. CCK8 and colony formation assays measured cell proliferation inhibition upon RPLP2 deletion, while transwell migration assays analyzed reduced cell motility. Lipid ROS and iron assays quantified ferroptosis markers to elucidate RPLP2’s regulation of FXN-mediated ferroptosis. Xenograft mouse models validated tumor suppression effects in vivo. Results: Here, we reveal that elevated RPLP2 expression is significantly correlated to unfavorable prognosis in DLBCL patients. In addition, we demonstrate that RPLP2 deletion dramatically reduces the cell proliferation and migration of DLBCL. Besides, knockdown of RPLP2 triggers ferroptosis via regulating ferroptosis suppressor FXN activity. Moreover, we discover that Destruxin b could target RPLP2 to suppress the development of DLBCL. Lastly, the combination of Destruxin b with Dox remarkably improves the anti-tumor effect. Conclusions: In general, the present study reveals the oncogenic role of RPLP2 in DLBCL, uncovers an unrecognized regulatory axis of ferroptosis, and identifies a specific inhibitor targeting RPLP2 to restrain DLBCL progression, suggesting that RPLP2 could be a potential target for DLBCL treatment. Full article

Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides long that do not encode proteins. Although many lncRNAs remain uncharacterized, they are known to play diverse regulatory roles in gene expression. A group of lncRNAs called natural antisense transcripts can form double-stranded structures with their sense partners due to sequence complementarity. These duplexes can become substrates for A-to-I RNA editing, an epitranscriptomic modification mediated by ADAR enzymes. RNA editing is known to influence transcript splicing, affect the resulting gene expression product or alter RNA stability, all of which can impact cancer cell biology. Here, we show a novel natural antisense transcript, UGGT1-AS1, that we have identified and characterized in terms of its cellular localization and sense partner interactions. Furthermore, we demonstrate that UGGT1-AS1 affects cell proliferation and regulates the stability of the UGGT1 sense transcript. Finally, using publicly available RNA sequencing data, we identify A-to-I RNA editing events in the protein-coding gene UGGT1 and further confirm them by RT-PCR and Sanger sequencing in MCF7 cell lines. We hypothesize that UGGT1-AS1 may act as a triggering factor for the A-to-I RNA editing process in its sense partner. Our findings highlight the regulatory role of UGGT1-AS1 and suggest its involvement in RNA editing and cancer biology. Full article