Search Results (378)

Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed–Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. This review synthesizes current knowledge on how metabolic alterations contribute to tumor survival, immune dysfunction, and therapeutic resistance in cHL. We discuss novel therapeutic approaches aimed at disrupting these processes and examine the potential of combining metabolic interventions with immune-based strategies—such as immune checkpoint inhibitors (CPIs), epigenetic modulators, bispecific antibodies, and CAR-T/CAR-NK cell therapies—which may help overcome resistance and enhance anti-tumor responses. Several agents are currently under investigation for their ability to modulate immune cell metabolism and restore effective immune surveillance. Altogether, targeting metabolic vulnerabilities within both tumor and immune compartments offers a promising, multifaceted strategy to improve clinical outcomes in patients with relapsed or refractory cHL. Full article

Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins-(IL-6 and IL-1β) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-κB/iNOS/COX-II/cytokines, PI3K/AKT, and BAX/BCL-2/caspase-3 signaling pathways. Full article

Current treatments against leukemia present several limitations, prompting the search for new therapeutic agents, particularly those derived from natural products. In this context, structural modifications were performed on the triterpene 3α,24-dihydroxylup-20(29)-en-28-oic acid (T1), isolated from Phoradendron wattii. Among the five derivatives obtained, 3α,24-dihydroxy-30-oxolup-20(29)-en-28-oic acid (T1c) exhibited the highest activity, with an IC₅₀ value of 12.90 ± 0.1 µM against THP-1 cells. T1c significantly reduced cell viability in both acute lymphoblastic leukemia (CCRF-CEM, REH, JURKAT, and MOLT-4) and acute myeloid leukemia (THP-1) cell lines, inducing apoptosis after 48 h of treatment, while showing minimal cytotoxicity toward normal mononuclear cells (MNCs). In silico molecular docking studies were conducted against three key protein targets: BCL-2 (B-cell lymphoma 2), EGFR (epidermal growth factor receptor, tyrosine kinase domain), and FLT3 (FMS-like tyrosine kinase 3). The lowest binding energies (kcal/mol) observed were as follows: T1–BCL-2: −10.12, EGFR: −12.75, FLT3: −14.05; T1c–BCL-2: −10.23, EGFR: −14.50, FLT3: −14.07; T2–BCL-2: −11.59, EGFR: −15.00, FLT3: −14.03. These findings highlight T1c as a promising candidate in the search for anti-leukemic drugs which deserves further study. Full article

Background/Objectives: Radiotherapy (RT) is a mainstay of clinical cancer therapy that causes broad immune responses. The complement system is a pivotal effector mechanism in the innate immune response, but the impact of RT is less well understood. This study investigates the interaction between RT and the complement system as a possible approach to improve immune responses in cancer treatment. Methods: Human solid cancer (lung, prostate, liver, breast cancer), lymphoma, and leukemia cells were irradiated using X-rays and treated with polyclonal antibodies or anti-CD20 monoclonal antibodies, respectively. Chromium release assay was applied to measure cell lysis after radiation with or without complement-activating antibody treatment. The expression of membrane-bound complement regulatory proteins (mCRPs; CD46, CD55, CD59), which confer resistance against complement activation, CD20 expression, apoptosis, and radiation-induced DNA double-strand breaks (γH2AX), was measured by flow cytometry. The radiosensitivity of tumor cells was assessed by colony-forming assay. Results: We demonstrate that RT profoundly impacts complement function by upregulating the expression of membrane-bound complement regulatory proteins (mCRPs) on tumor cells in a dose- and time-dependent manner. Impaired complement-mediated tumor cell lysis could thus potentially contribute to radiotherapeutic resistance. We also observed RT-induced upregulation of CD20 expression on lymphoma and leukemic cells. Notably, complement activation prior to RT proved more effective in inducing RT-dependent early apoptosis compared to post-irradiation treatment. While complement modulation does not significantly alter RT-induced DNA-damage repair mechanisms or intrinsic radiosensitivity in cancer cells, our results suggest that combining RT with complement-based anti-cancer therapy may enhance complement-dependent cytotoxicity (CDC) and apoptosis in tumor cells. Conclusions: This study sheds light on the complex interplay between RT and the complement system, offering insights into potential novel combinatorial therapeutic strategies and a potential sequential structure for certain tumor types. Full article

Background/Objectives: Reprogramming of the cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP) is a small alkylating agent that functions as an anti-metabolite, targeting key substrates in cancer metabolism and demonstrating antitumor activity across multiple cancer types. However, unformulated 3BP is associated with significant toxicity. This study investigates the efficacy of KAT/3BP, a clinical derivative of 3BP currently in phase 1 trials for hepatocellular carcinoma, in preclinical lymphoma models. Results: In vitro, KAT/3BP exhibited cytotoxic activity across 12 lymphoma cell lines—including diffuse large B-cell lymphoma and mantle cell lymphoma—with a median IC₅₀ of 3.7 μM. It also remained effective against lymphoma cell lines with acquired resistance to FDA-approved therapies. In vivo, treatment with KAT/3BP led to reduced tumor size in a syngeneic mouse model, with the combination of oral and intratumoral administration showing the greatest efficacy. Furthermore, KAT/3BP demonstrated synergistic activity when combined with standard lymphoma therapies such as bendamustine and R-CHOP. Conclusions: Our findings highlight the potential of KAT/3BP as a novel therapeutic option, either as a single agent or in combination regimens, for treating lymphomas. Full article

T cells equipped with chimeric antigen receptors (CARs) have evolved into an essential pillar of lymphoma therapy, reaching second-line treatment. In solid cancers, however, a dearth of lasting CAR T cell activation poses the major obstacle to achieving a substantial and durable anti-tumor response. To extend T cell cytotoxic capacities, we engineered CAR T cells to constitutively release an immunostimulatory variant of soluble SLAMF6. While wild-type SLAMF6 induces T cell exhaustion, CAR T cells with the soluble Δ17-65 SLAMF6 variant exhibited refined, CAR redirected functionality compared to canonical CAR T cells. CD28-ζ CAR T cells releasing soluble SLAMF6 increased IFN-γ secretion and augmented CD25 upregulation on CD4⁺ CAR T cells upon CAR engagement by pancreatic carcinoma and melanoma cells. Moreover, under conditions of repetitive antigen encounter, SLAMF6-secreting CAR T cells evinced superior cytotoxic capacity in the long term. Mechanistically, SLAMF6-secreting CAR T cells showed predominantly a central memory phenotype, a PD-1^- TIGIT^- double negative profile, and reduced expression of exhaustion-related transcription factors IRF-4 and TOX with augmented amplification and persistence capacities. Overall, CAR T cells engineered with the release isoform 2 SLAMF6 establish an auto-stimulatory loop with the potential to boost the cytolytic attack against solid tumors. Full article

Terpenoids are a large group of molecules present in several plant species and in many essential oils reported with cytotoxic and anticancer properties. The aim of this study was to evaluate the anticancer activity of eleven acyclic terpenes; seven monoterpenoids: geranyl acetate (C1), geranic acid (C2), citral (C3, mixture of neral and geranial), geraniol (C4), methyl geranate (C5), nerol (C6) and citronellic acid (C7); two sesquiterpenes: farnesal (C8) and farnesol (C9); and one triterpene: squalene (C10), using in vivo, in vitro, and in silico models. Anti-lymphoma activity was evaluated using male Balb/c mice inoculated with U-937 cells. Cytotoxic activity was evaluated using the WST-1 method. Computer tools were used to obtain a molecular docking study, measuring pharmacokinetic and toxicological properties of the acyclic terpenoids with greater antitumor activity. The results showed that the terpenoids with the highest cytotoxic and nodal growth inhibitory activity were C3, C4, C6, and C9, and their effects were better compared to MTX. The data obtained suggest that the anti-lymphoma activity could be due to the presence of the aldehyde, hydroxyl, and acetate groups in the C1 of the monoterpenes and sesquiterpenes evaluated. The theoretical results obtained from molecular docking showed that geranial (C3A), neral (C3B), C9, and C6 terpenoids obtained a higher affinity for the HMG-CoA reductase enzyme and suggest that it could be a target to induce anti-lymphoma activity of bioactive terpenoids. Our study provides evidence that C3, C6, and C9 could be potential anticancer agents for the treatment of histiocytic lymphoma. Full article

Mogamulizumab is a humanized monoclonal antibody that targets C-C chemokine receptor 4 (CCR4) present on certain T cells in lymphomas and leukemias. This antibody-based therapy has demonstrated efficacy in treating various cutaneous T cell lymphomas (CTCLs), including mycosis fungoides and Sézary syndrome, through the depletion of CCR4-expressing T cells by antibody-dependent cellular cytotoxicity (ADCC). However, the precise epitope and binding mode of mogamulizumab responsible for its augmented ADCC activity remain undisclosed. Here, X-ray crystallographic studies of mogamulizumab in complex with a 28-residue N-terminal peptide indicated that SIYSNYYLYES (residues 14–24) would constitute the antibody epitope. Another high-resolution structure, using a short core peptide of these 11 residues, has elucidated unambiguous electron density for the bound peptide, confirming consistent binding for both peptides. This linear epitope is located in the membrane-proximal region of CCR4, facilitating the Fc-mediated effector functions, including ADCC. The structures also provide insights into the molecular basis for the resistance of the CCR4 L21V variant to mogamulizumab, which is due to a lack of structural complementarity with mogamulizumab binding. Understanding the structural basis for the mechanism of action of mogamulizumab is crucial for optimizing anti-CCR4 therapeutics to improve treatment outcomes for patients with these challenging diseases. 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

Azvudine (FNC) is a novel cytidine analogue that is widely used in the treatment of infectious diseases such as AIDS and COVID-19. Previous studies have demonstrated its anticancer activity in various cancer cell lines, including non-Hodgkin’s lymphomas and lung adenocarcinoma cell lines. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms remain unclear. This study aimed to investigate the anti-epithelial–mesenchymal transition (anti-EMT) activity of FNC and evaluate its potential application in HCC treatment. We found that FNC significantly inhibits the migration of the liver cancer cell line Huh7 by downregulating key EMT markers, such as matrix metalloproteinases (MMPs) and E-cadherin, at both the transcriptional and protein expression levels. Notably, we found that FNC inhibits HEY proteins, particularly HEY1, a transcriptional regulator of the Notch signalling pathway that is overexpressed in approximately 50% of HCC patients. To identify the primary target of FNC, microscale thermophoresis (MST) and molecular dynamics (MD) simulations were performed, revealing that FNC directly binds to Jagged1. This study provides valuable insights into the therapeutic potential of FNC in HCC treatment and elucidates its underlying mechanisms. Full article

Salinomycin (SAL), originally identified for its potent antibacterial properties, has recently garnered attention for its remarkable activity against a variety of cancer types. Beyond its direct cytotoxic effects on cancer cells, SAL can also enhance the efficacy of anti-CD20 immunotherapy in B-cell malignancies, both in vitro and in vivo. Despite these promising findings, the precise molecular mechanisms underlying SAL’s anticancer action remain poorly understood. Here, we demonstrate that even at low concentrations (0.25–0.5 mM), SAL disrupts mitochondrial membrane potential and induces oxidative stress in Burkitt lymphoma. Further investigations uncovered that SAL shifts cellular metabolism from mitochondrial respiration to aerobic glycolysis. Additionally, metabolomic profiling identified SAL-induced arginine depletion as a key metabolic alteration. These findings provide new insights into SAL’s multifaceted mechanisms of action and support its potential as an adjunctive therapy in cancer treatment. Full article

Background: Allergic rhinitis (AR) is triggered by immunoglobulin E (IgE)-mediated immune responses to airborne allergens. Recent studies highlight the pivotal role of T follicular helper 2 (Tfh2) cells in IgE production. Interleukin-37 (IL-37) has emerged as an intrinsic modulator of innate immunity and inflammatory processes. We aimed to investigate the regulatory effect of IL-37 on Tfh2 cells in the pathogenesis of AR. Methods: Blood samples were collected from AR patients and controls. The IL-37 levels and the frequency of Tfh2 cells were detected by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, respectively. The isolated Tfh2 cells were cultured or cocultured with naive B cells. The regulatory effects of IL-37 on Tfh2/B cells were assessed using ELISA, quantitative real-time polymerase chain reaction (qRT-PCR). Mouse models of ovalbumin (OVA)-induced AR were established to explore the effect of IL-37 in vivo. Results: IL-37 suppressed the production of IL-4 and IL-21 by Tfh2 cells and downregulated C-X-C chemokine receptor type 5 (CXCR5) and B-cell lymphoma 6 protein (Bcl6) mRNA expression while upregulating B lymphocyte-induced maturation protein 1 (Blimp1) and signal transducers and activators of transduction5 (STAT5) mRNA. IL-37 decreased IgE production by B cells significantly, and the addition of anti-IL-18 receptor α alleviated this effect. In mouse models, IL-37 reduced nasal rubbing, sneezing, eosinophil counts, OVA-specific IgE, and Tfh2 proportions. Conclusions: IL-37 plays a crucial role in modulating Tfh2 cell responses in AR, suggesting a potential therapeutic target for this condition. Full article

Kujigamberol, a dinorlabdane compound isolated from Kuji amber, exerts multiple biological effects, including anti-allergic and anti-inflammatory activities. The present study demonstrated that kujigamberol inhibited cytokine production by T cells. In response to a phorbol 12-myristate 13-acetate (PMA) and ionomycin (IM) stimulation, kujigamberol suppressed interferon-γ (IFN-γ) and interleukin-2 (IL-2) mRNA expression in murine T-cell lymphoma BW5147 cells stably transfected with the T-box transcription factor eomesodermin. IL-4 and Fas ligand mRNA expression was also inhibited by kujigamberol. In the murine cytotoxic T-cell line CTLL-2, kujigamberol more strongly decreased IFN-γ mRNA expression induced by IM alone than that induced by the combination of PMA and IM. A luciferase reporter assay showed that kujigamberol preferentially reduced nuclear factor of activated T cell (NFAT)-dependent transcription in human embryonic kidney 293T cells. Unlike the calcineurin inhibitor FK506, kujigamberol did not markedly affect NFATc2 protein levels in BW5147 cells but interfered with the binding of NFATc2 to the IFN-γ and IL-2 promoters. These results indicate that kujigamberol inhibited IFN-γ and IL-2 mRNA expression by preventing the binding of NFATc2 to their promoters; therefore, it has potential as an immunosuppressive agent. Full article

Lymphoma is one of the malignant tumors that significantly threatens human health. Quadrigemine I, an indole alkaloid derived from the leaves of Psychotria pilifera, has been studied for its potential anti-tumor properties, but its mechanisms remain poorly understood. The CCK-8 assay was used to determine the cytotoxic effect of quadrigemine I on lymphoma cells. Flow cytometry was employed to analyze apoptosis and reactive oxygen species (ROS) levels in these cells. DNA damage was assessed by the comet assay, and the underlying mechanisms were investigated using RNA sequencing (RNA-seq) and real-time quantitative PCR (RT-qPCR). The anti-tumor activity of quadrigemine I was evaluated in tumor xenograft mice. Quadrigemine I suppressed lymphoma cell proliferation with an IC₅₀ of 0.46 µM. It induced apoptosis, promoted ROS generation, and caused DNA damage in tumor cells. RNA-seq analysis revealed that the significantly differentially expressed genes were notably enriched in the ErbB, p53, and apoptosis signaling pathways. RT-qPCR demonstrated altered expression levels of key genes in the aforementioned pathways. In vivo, quadrigemine I significantly inhibited tumor growth in xenograft mice by increasing apoptosis in tumor tissues, with reduced Ki-67 and Bcl-2 expression and elevated cleaved caspase-3 levels. Quadrigemine I may serve as a novel anti-tumor agent for lymphoma therapy. Full article

Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody–drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities—particularly cytokine release syndrome (CRS)—and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments. Full article