Search Results (728)

Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. The search for effective, new antineoplastic drugs with fewer side effects for the treatment of CRC continues, with marine-derived compounds emerging as promising candidates. Objectives: This study investigates the anticancer potential of Frondanol, a nutraceutical derived from the Atlantic Sea cucumber Cucumaria frondosa, known for its potent anti-inflammatory properties. Methods: Two human CRC cell lines, Caco-2 and HT-29, were used to test the effects of Frondanol using various in vitro approaches. Results: Frondanol significantly inhibited cell viability in a dose- and time-dependent manner. At a 1:10,000 dilution, viability decreased to around 30% in Caco-2 and 20% in HT-29 after 24 h, dropping to nearly 5% at 48 h. Furthermore, a clonogenic assay showed around 50% reduction in colony formation in both cell lines. Flow cytometry-based Annexin V staining revealed that Frondanol increased early apoptosis to ~5.2% in Caco-2 and ~9.4% in HT-29 cells, while cell cycle analysis showed accumulation of the sub G0 (apoptotic) phase increasing from 1.5% to 14.7% (Caco-2) and from 1.9% to 23.8% (HT-29). At the molecular level, Frondanol treatment significantly decreased anti-apoptotic protein B-cell lymphoma (Bcl)-2 expression while increasing the expression of the proapoptotic protein Bcl-2-associated X-protein. Additionally, Frondanol markedly induced cytochrome c release from the mitochondria and activated caspase-9, caspase-7, and caspase-3 after treatment, alongside cleavage of the caspase-3 substrate poly (ADP-ribose) polymerase. Frondanol inhibited 5-lipoxygenase activity, further contributing to its anticancer effects. Conclusions: In conclusion, Frondanol inhibits CRC cell proliferation and induces apoptosis through the mitochondrial pathway in vitro, suggesting that it is a potential nutraceutical for the prevention of human colorectal cancer or a valuable source of anticancer compounds. Full article

Colon cancer (CC) is a common malignancy characterized by poor prognostic outcomes and considerable mortality. Oxaliplatin (OXP) is commonly used in the treatment of CC; however, its efficacy may be limited by side effects and the development of resistance. β-sitosterol (β-Sit), a phytosterol derived from plants, has been documented to be effective in the treatment of tumors. This study aimed to investigate the potential of β-Sit to enhance the antitumor efficacy of OXP in COLO-205 cells, focusing on apoptosis induction and suppression of the vascular endothelial growth factor A (VEGF-A)/survival pathway. Molecular docking studies were performed to assess the binding affinity of β-Sit with the target proteins B-cell lymphoma 2 (Bcl-2), phosphoinositide 3-kinase (PI3K), and VEGF receptor-2 (VEGFR-2). COLO-205 cells were treated with OXP, β-Sit, or a combination of OXP + β-Sit for 48 h. The combination treatment substantially lowered the IC₅₀ achieved with 3.24 µM of OXP and 36.01 µM of β-Sit, compared to 25.64 µM for OXP alone and 275.9 µM for β-Sit alone, demonstrating a pronounced synergistic impact. The combined therapy altered the cell cycle distribution by decreasing the number of cells in the G0/G, S, and G2/M phases, coupled with an increase in the Sub-G1 population. Furthermore, apoptosis was augmented by a shift in cell death from necrosis to late apoptosis, as indicated by an increased BAX/BCL2 ratio relative to each treatment alone. Moreover, the inhibitory effect on angiogenesis was enhanced via the reduction of VEGF-A, and β-catenin and nuclear factor κB (NF-κB-p65) were suppressed, thereby preventing the growth and survival of resistant cancer cells. Additionally, molecular docking supported high binding affinities of β-Sit to Bcl-2, PI3K, and VEGFR-2. This study highlights the potential of β-Sit to enhance the anti-cancer efficacy of OXP in CC. Full article

Background/Objectives: Three-dimensional (3D) in vitro cell culture models have recently stimulated great interest since they may have more pre-clinical value than conventional in vitro 2D models. In fact, 3D culture models may mimic the in vivo biophysical 3D structure of tumors and cell-to-cell interaction, thereby representing a more useful approach to testing drug responses. In this study we have developed a 3D culture model of an EBV+/CD30+cell line, D430B, previously characterized as an Anaplastic Large Cell Lymphoma of B phenotype (B-ALCL), to determine the cytotoxic activity of the antibody–drug conjugate Brentuximab Vedotin. Methods: By using of ultra-low attachment plates, we developed D430B spheroids that appeared particularly homogenous in terms of growth and size. Results: Brentuximab Vedotin treatment (1 to 20 μg/mL) turned out to be significantly cytotoxic to these cells, while the addition of the anti-CD20 chimeric antibody Rituximab (10 μg/mL) appeared almost ineffective, even though these cells express CD20. Moreover, when we co-cultured D430B cells with stromal cells (HS5), to re-create a microenvironment representative of neoplastic cell/mesenchymal cell interactions within the lymph node, we observed a significant, although faint, protective effect. Conclusions: This simple and reproducible method of generating D430B-ALCL spheroids to evaluate their response to Brentuximab Vedotin treatment, as here described, may provide a valuable preliminary tool for the future pre-clinical screening of patients’ primary lymphoma cells or the development of novel therapies for this type of pathology and related diseases. Full article

L-asparaginase (L-ASNase) is a vital enzymatic drug widely used for treating acute lymphoblastic leukemia (ALL) and certain lymphomas. However, its clinical application is often limited by a short plasma half-life, pronounced immunogenicity, and systemic toxicities. To address these challenges, we recently developed conjugates of L-ASNase with cationic polymers, enhancing its cytostatic activity by increasing enzyme binding with cancer cells. The present study focuses on the development of liposomal formulations of E. coli L-asparaginase (EcA) and its conjugates with cationic polymers: the natural oligoamine spermine (spm) and a synthetic polyethylenimine–polyethyleneglycol (PEI-PEG) copolymer. This approach aims to improve enzyme encapsulation efficiency and stability within liposomes. Various formulations—including EcA conjugates with polycations incorporated into 100 nm and 400 nm phosphatidylcholine/cardiolipin (PC/CL, 80/20) anionic liposomes—were synthesized as a delivery system of high enzyme load. Fourier Transform Infrared (FTIR) spectroscopy confirmed successful enzyme association with liposomal carriers by identifying characteristic changes in the vibrational bands corresponding to both protein and lipid components. In vitro release studies demonstrated that encapsulating EcA formulations in liposomes more than doubled their half-release time (T_1/2), depending on the formulation. Cytotoxicity assays against Raji lymphoma cells revealed that liposomal formulations, particularly 100 nm EcA-spm liposomes, exhibited markedly superior anti-proliferative activity, reducing cell viability to 4.5%, compared to 35% for free EcA. Confocal Laser Scanning Microscopy (CLSM) provided clear visual and quantitative evidence that enhanced cellular internalization of the enzyme correlates directly with its cytostatic efficacy. Notably, formulations showing higher intracellular uptake produced greater cytotoxic effects, emphasizing that hydrolysis of asparagine inside cancer cells, rather than extracellularly, is critical for therapeutic success. Among all tested formulations, the EcA-spermine liposomal conjugate demonstrated the highest fluorescence intensity within cells providing enhanced cytotoxicity. These results strongly indicate that encapsulating cationically modified L-ASNase in liposomes is a highly promising strategy to improve targeted cellular delivery and prolonged enzymatic activity. This strategy holds significant potential for developing more effective and safer antileukemic therapies. Full article

Eleutheroside E (EE), a natural compound, shows promise in mitigating cellular senescence—a key factor in skin aging—though its mechanisms remain incompletely understood. This study integrated network pharmacology, molecular docking, and cellular experiments to explore the protective effects and mechanistic basis of EE against D-galactose (D-gal)-induced senescence in human skin fibroblasts (HSFs). Network pharmacology analyses suggested EE’s involvement in inflammation-related pathways, especially phosphatidylinositol 3-kinase and protein kinase B (PI3K-AKT) and hypoxia-inducible factor 1 (HIF-1) signaling, which were corroborated by molecular docking revealing strong binding affinities between EE and key targets such as hypoxia-inducible factor 1-alpha (HIF1A), AKT serine/threonine kinase 1 (AKT1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PI3Kγ), and interleukin-6 (IL-6). Cellular assays showed that EE markedly lowered oxidative stress markers, including reactive oxygen species (ROS) and malondialdehyde (MDA), reduced senescence-associated beta-galactosidase (SA-β-gal) activity, and boosted antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). Additionally, EE dose-dependently inhibited apoptosis and downregulated PI3K/AKT phosphorylation as well as the B-cell lymphoma 2-associated X protein/B-cell lymphoma-2 (Bax/Bcl-2) ratio. These findings suggest that EE alleviates cellular senescence in HSFs mainly via the PI3K/AKT pathway by attenuating oxidative stress and apoptosis, highlighting its potential as a therapeutic agent for anti-aging strategies. Full article

High-dose therapy with cytarabine (araC) is a standard treatment for aggressive non-Hodgkin lymphomas, but its efficacy is limited by rapid enzymatic degradation. To overcome this, araC was conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers to form linear and star-like nanomedicines using six different spacers: 3-aminopropanoyl, 5-pentanoyl, 6-aminohexanoyl, 4-aminobenzoyl, glycyl, and diglycyl. The conjugates contained 12.5–14.7 wt% araC and exhibited distinct hydrolytic release profiles at pH 7.4. LC1 (3-aminopropanoyl) and LC6 (diglycyl) released the drug most rapidly (~80% bound after 72 h), and LC2, LC3, and the star conjugate SC1 showed intermediate stability (~90%), while LC4 (4-aminobenzoyl) was most stable (~95%). In vivo, all conjugates markedly suppressed tumor growth in patient-derived xenograft models of mantle cell and Burkitt lymphoma compared with free araC. LC1 and LC2 provided the most durable tumor control, delaying regrowth beyond 40 days, and SC1 achieved comparable efficacy at a reduced araC-equivalent dose (2 mg/mouse vs. 3 mg/mouse for linear conjugates). These results demonstrate that spacer structure critically influences drug release and identify LC1 and LC2 as promising candidates for further development in lymphoma therapy. Full article

Oxidative stress-induced mitochondrial dysfunction and apoptosis are critical factors in the pathogenesis of neurodegenerative diseases. This study investigated the synergistic neuroprotective effects of anthocyanin-enriched Morus alba L. extract combined with vitamin C (MAC) against hydrogen peroxide (H₂O₂)-induced oxidative stress in SH-SY5Y neuronal cells. Exposure to H₂O₂ triggered excessive reactive oxygen species (ROS) production and apoptosis, whereas treatment with MAC markedly alleviated these effects. Biochemical analyses revealed that MAC significantly reduced malondialdehyde (MDA) and enhanced the activities of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), thereby contributing to improved redox balance. Furthermore, MAC modulated apoptosis-related signaling by upregulating extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), while downregulating the pro-apoptotic protein Bcl-2-associated X (BAX) and cleaved caspase-3. Collectively, these findings demonstrate that MAC acts synergistically as a promising nutraceutical ingredient, supporting the development of functional foods for the prevention or mitigation of oxidative stress-related neurodegenerative disorders. Full article

Burkitt lymphoma (BL) is a rare, aggressive B-cell lymphoma that is characterized by rapid tumor proliferation and frequent extra-nodal involvement. While prompt diagnosis and initiation of highly intensive chemotherapy results in cure rates over 90% in children and adolescents, outcomes in adults are more modest, as comorbidities and advancing age may compromise treatment tolerability. In recent years, intermediate-intensity regimens have been developed for BL. These are highly effective in patients of all ages and associated with significantly less treatment-related toxicity compared to traditional high-dose chemotherapy. This was demonstrated in a recent randomized study of dose-intensive R-CODOX-M/R-IVAC compared to the reduced-intensity DA-EPOCH-R regimen, which was associated with equivalent outcomes but with significantly fewer side effects. Regardless of the chemotherapy platform, CNS involvement at baseline predicts a significantly inferior outcome, and the development of an optimal approach for these patients is an area of unmet need in BL therapeutics. Patients with relapsed or refractory disease following frontline therapy have very short survival times, as currently available salvage options are largely ineffective. In this regard, novel agents such as anti-CD19 CAR-T cells and bi-specific antibodies are under development in BL. It is hoped that progress in novel drug development, alongside improved understanding of BL biology, to further elucidate its genetic and epigenetic vulnerabilities, will lead to improved outcomes for patients in the future. Full article

Background: Cancer treatments can damage the ovaries, with implications for fertility and reproductive lifespan. Therefore, a useful biomarker for fertility preservation counseling is needed, and anti-Müllerian hormone (AMH) measurement provides an index of the treatment gonadotoxicity. The debate is currently open as to whether the ovarian reserve may already be reduced before exposure to anticancer therapy. Therefore, our aim was to evaluate the influence of cancer on AMH levels. Methods: The present retrospective, cross-sectional study was carried out at the Centre for Reproductive Medicine and IVF Unit in Conversano, ASL Bari (Bari, Italy). All data were collected between 2019 and 2023. The serum AMH levels of 175 female patients with cancer were compared with those of non-cancer patients of reproductive age, just before starting chemotherapy. Results: AMH levels in women with breast cancer did not differ significantly from those in women without breast cancer (2.83 [0.81–9.15] ng/mL vs. 2.58 [0.7–9.2] ng/mL; p-value = 0.23). The AMH levels of the non-Hodgkin or Hodgkin lymphoma group were significantly lower than those of the non-cancer group (1.9 [0.7–7.0] vs. 3.2 [0.9–10.00] ng/mL; p-value < 0.05). Conclusions: AMH levels of non-Hodgkin or Hodgkin lymphoma patients were already reduced before cancer therapy compared to those of non-cancer patients. These results may be related to the systemic effect of the lymphoma, compared with other types of cancer. Full article

Background/Objectives: Breast cancer remains one of the leading causes of cancer-related mortality in women worldwide, highlighting the urgent need for effective and less toxic therapeutic strategies. Thymoquinone (TQ), a bioactive phytochemical derived from Nigella sativa, possesses antioxidant and anticancer activities. Methotrexate (MTX), a widely used folate antagonist, is an established chemotherapeutic agent but is limited by toxicity and resistance. This study aimed to investigate the potential synergistic effects of TQ and MTX in estrogen receptor-positive MCF-7 breast cancer cells. Methods: MCF-7 cells were exposed to TQ (0–100 μM), MTX (0–10 μM), and their combinations for 24–72 h. Cell viability was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and drug interactions were evaluated using the Chou–Talalay method. Apoptosis was quantified by Annexin V/Propidium Iodide (PI) flow cytometry, and cell cycle distribution was analyzed by PI staining. Intracellular reactive oxygen species (ROS) generation was measured using a 2′,7′-Dichlorofluorescin diacetate (DCFH-DA) assay, while antioxidant enzyme (superoxide dismutase (SOD), catalase (CAT)) activities were quantified spectrophotometrically. Gene expression of Bax, Bcl-2, NF-κB, MMP-2, and MMP-9 was determined by Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Results: TQ and MTX each reduced cell viability in a dose- and time-dependent manner, while combination treatment significantly enhanced cytotoxicity compared with single agents (p < 0.01). Combination Index (CI) values < 1 confirmed a synergistic interaction, particularly at 50 μM TQ + 5 μM MTX and 100 μM TQ + 10 μM MTX. Combination therapy increased total apoptosis up to 83.6%, markedly elevated the Bax/Bcl-2 ratio, and enhanced caspase-3 activation. Cell cycle analysis revealed pronounced G2/M arrest. ROS levels increased approximately six-fold, accompanied by significant suppression of SOD and CAT activities. qRT-PCR results demonstrated upregulation of pro-apoptotic Bax and downregulation of anti-apoptotic B-cell lymphoma 2 (Bcl-2), nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-2, and MMP-9. Conclusions: TQ potentiates the anticancer activity of MTX in MCF-7 breast cancer cells by synergistically inducing apoptosis, oxidative stress, and cell cycle arrest while suppressing metastasis-related genes. This combination may represent a promising therapeutic strategy for breast cancer, warranting further validation in in vivo and clinical studies. Full article

G-quadruplexes have been identified as a promising anti-cancer target because of their ability to modulate the stability of mRNAs encoding oncogenes, tumor suppressor genes, and other potential therapeutic targets. Deregulation of DNA damage and Unfolded Protein Response pathways in cancer cells may create vulnerabilities that can be exploited therapeutically. Previous studies have shown variations in the relative expression of DDR and UPR components in canine lymphoma and leukemia cell lines CLBL-1, CLB70, and GL-1. In the present study, we report the presence of G-quadruplex structures in these canine cell lines. Downregulation of the expression of DDR and UPR components at the mRNA level was observed in the CLBL-1 and CLB70 cell lines after stabilization of G4 structures using the ligand PhenDC3. In contrast, in GL-1 cells, important components of the DDR pathway, such as PARP1, GADD45A, and PIK3CB were upregulated in response to PhenDC3 treatment. Downregulation of DDIT4 mRNA expression, which encodes an important UPR component, was detected in the CLBL-1 and GL-1 cell lines after PhenDC3 exposure. These results suggest that G4 structures can be used to manipulate the expression of potential targets to treat lymphoma in dogs. A substantial enrichment of DNA replication and pyrimidine metabolism pathways was found in the GL-1 cell line after G4 stabilization. This finding suggests that PhenDC3 may induce DNA replication stress in this cell line. Collectively, these results support the feasibility of employing canine cancer cells as a model system to investigate the role of G-quadruplex structures in cancer. Full article

Peritoneal carcinomatosis (PC) and malignant pleural effusions (MPE) are two common complications of cancers metastatic to the respective body cavities. A PC diagnosis indicates metastasis to the tissue lining the abdominal cavity and is most common in patients with gastrointestinal and gynecological cancers. It is often accompanied by ascites, an accumulation of serous fluid in the abdomen. MPE presents as the accumulation of fluid in the space between the lungs and chest wall. It is a common terminal event in patients diagnosed with breast cancer, lung cancer, lymphoma, and mesothelial cancers, and less commonly, in a wide variety of other epithelial cancers. Due to the aggressive nature of cavitary tumors, the outcome of current treatments for both PC and MPE remains bleak. Although PC and MPE are characteristically affected by different sets of primary tumors (lung/breast/mesothelioma for MPE and gynecologic/gastrointestinal for PC), their environments share common cytokines and cellular components. Owing to the unique cytokine and chemokine content, this environment promotes aggressive tumor behavior and paradoxically both recruits and suppresses central memory and effector memory T cells. The cellular and secretomic complexity of the cavitary tumor environment renders most currently available therapeutics ineffective but also invites approaches that leverage the robust T-cell infiltrate while addressing the causes of local suppression of anti-tumor immunity. Interactions between the heterogeneous components of the tumor environment are an area of active research. We highlight the roles of the immune cell infiltrate, stromal cells, and tumor cells, and the soluble products that they secrete into their environment. A more comprehensive understanding of the cavitary tumor environment can be expected to lead to better immunotherapeutic approaches to these devastating conditions. Full article

Lymphomas remain a significant cause of morbidity and mortality among patients living with HIV. Although the introduction of antiretroviral therapy has led to a reduction in the incidence of AIDS-related lymphomas (ARL) and an overall improvement in prognosis, these malignancies continue to pose a considerable clinical challenge. Beyond the inherent complexity of lymphoma treatment itself, the management of comorbidities, particularly infections, represents a therapeutic obstacle. Here, we review the published evidence on ARL complicated by COVID-19. Despite the fact that nearly 800 million confirmed cases of SARS-CoV-2 infection have been reported so far, only five cases of ARL and COVID-19 have been published, among whom most patients experienced a mild course of SARS-CoV-2 infection, with only one case progressing to severe COVID-19 that required oxygen therapy and prolonged hospitalization. Additionally, we present another case of a 49-year-old male patient with newly diagnosed ARL, Epstein–Barr virus (EBV)-positive, diffuse large B-cell lymphoma, not otherwise specified, complicated by prolonged SARS-CoV-2 infection. Although initially asymptomatic, the patient subsequently experienced transient respiratory failure. Despite administration of molnupiravir, both SARS-CoV-2 antigen and RT-qPCR tests remained positive for a minimum of 113 days. The prolonged SARS-CoV-2 infection, in conjunction with other opportunistic infections, impeded the delivery of adequate chemotherapy dose intensity and contributed to disease progression and ultimately the patient’s death. This case and review of the literature underscores the diversity of the clinical course of SARS-CoV-2 infection in patients with ARL and highlights the associated challenges in delivering optimal anti-lymphoma therapy in those patients. Full article

Aldehyde dehydrogenase 1A1 (ALDH1A1) has emerged as a significant biomarker associated with tumor progression, chemoresistance, and poor prognosis in various cancers, including breast, lung, prostate, and lymphoma. Current diagnostic methods for ALDH1A1, such as flow cytometry and ELISA, are limited by long detection times, the need for labeling, and a reduced sensitivity in complex biological matrices. This study presents a novel optical fiber biosensor based on magnesium silicate nanoparticle-doped fibers for the label-free detection of ALDH1A1. The biosensor design incorporated protein G for enhanced antibody orientation and binding efficiency and anti-ALDH1A1 antibodies for specific recognition. Several sensor configurations were fabricated using a semi-distributed interferometer (SDI) format, and their performances were evaluated across a wide concentration range (10 fM–100 nM) in both phosphate-buffered saline (PBS) and fetal bovine serum (FBS). Our findings demonstrated that the inclusion of protein G significantly improved sensor sensitivity and reproducibility, achieving a limit of detection (LoD) of 172 fM in PBS. The sensor also maintained a positive response trend in FBS, indicating its potential applicability in clinically relevant samples. This work introduces the first reported optical fiber biosensor for soluble ALDH1A1 detection, offering a rapid, label-free, and highly sensitive approach suitable for future use in cancer diagnostics. Full article

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma characterized by a profoundly immunosuppressive tumor microenvironment. PD-L1 overexpression by tumor cells is a recognized immune escape mechanism and may underlie resistance to cellular therapies, including CAR T-cell therapy. We report a case of a 29-year-old woman with refractory stage IV-B THRLBCL treated with anti-CD19 CAR T-cell therapy (varnimcabtagene autoleucel), who achieved an initial response (day +28) but experienced disease progression by day +100 despite robust CAR T-cell expansion. Peripheral blood analysis revealed persistent absolute B-cell aplasia, while bone marrow biopsy confirmed CD19-positive disease. Comparative immunohistochemistry demonstrated markedly increased PD-L1 expression in post-CAR T-cell samples, suggesting adaptive immune resistance via PD-1/PD-L1-mediated CAR T-cell inhibition. Nivolumab was initiated at month +4 to overcome this checkpoint-mediated resistance. Notably, a complete metabolic response was documented on PET/CT after four doses of nivolumab (month +6). The patient remains in sustained remission, with persistent B-cell aplasia, four years post-intervention. This case provides clinical and pathological evidence supporting the use of immune checkpoint blockade to rescue CAR T-cell efficacy, highlighting the potential of this synergistic approach in THRLBCL and possibly other B-cell malignancies exhibiting similar immune evasion. Full article