Establishment of cluster of differentiation 20 immobilized cell membrane chromatography for the screening of active antitumor components in traditional Chinese medicine.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of malignant tumors occurring in B or T lymphocytes, and no small molecule-positive drugs to treat NHL have been marketed. Cluster of differentiation 20 (CD20) is an important molecule regulating signaling for the life and differentiation of B lymphocytes and possesses the characteristics of a drug target for treating NHL. 2-Methoxyestradiol induces apoptosis in lymphoma Raji cells and CD20 protein is highly expressed by Raji lymphoma cells. Therefore, in this study, a CD20-SNAP-tag/CMC model was developed to validate the interaction of 2-methoxyestradiol with CD20. 2-Methoxyestradiol was used as a small molecule control compound, and the system was validated for good applicability. The cell membrane chromatography model was combined with high-performance liquid chromatography ion trap time-of-flight mass spectroscopy (HPLC-IT-TOF-MS) in a two-dimensional system to successfully identify, analyze, and characterize the potential active compounds of Schisandra chinensis (Turcz.) Baill. extract and Lysionotus pauciflorus Maxim. extract, including Schisandrin A, Schizandrol A, Schizandrol B, Schisantherin B, and Nevadensin, which can act on CD20 receptors. The five potential active compounds were analyzed by non-linear chromatography. The thermodynamic and kinetic parameters of their interaction with CD20 were also analyzed, and the mode of interaction was simulated by molecular docking. Their inhibitory effects on lymphoma cell growth were assessed using a Cell Counting Kit-8 (CCK-8). Nevadensin and Schizandrin A were able to induce apoptosis in Raji cells within a certain concentration range. In conclusion, the present experiments provide some bases for improving NHL treatment and developing small molecule lead compounds targeting CD20 with low toxicity and high specificity.

Development and validation of a model to predict acute kidney injury following high-dose methotrexate in patients with lymphoma.

STUDY OBJECTIVE: To develop and validate a model for predicting acute kidney injury (AKI) after high-dose methotrexate (HDMTX) exposure. DESIGN: Retrospective analysis. SETTING: Multisite integrated health system throughout Minnesota and Wisconsin. PATIENTS: Adult patients with lymphoma who received HDMTX as a 4-h infusion. MEASUREMENTS AND MAIN RESULTS: LASSO methodology was used to identify factors available at the outset of therapy that predicted incident AKI within 7 days following HDMTX. The model was then validated in an independent cohort. The incidence of AKI within 7 days following HDMTX was 21.6% (95% confidence interval (CI) 18.4%-24.8%) in the derivation cohort (435 unique patients who received a total of 1642 doses of HDMTX) and 15.6% (95% CI 5.3%-24.8%) in the validation cohort (55 unique patients who received a total of 247 doses of HDMTX). Factors significantly associated with AKI after HDMTX in the multivariable model included age ≥ 55 years, male sex, and lower HDMTX dose number. Other factors that were not found to be significantly associated with AKI on multivariable analysis, but were included in the final model, were body surface area, Charlson Comorbidity Index, and estimated glomerular filtration rate. The c-statistic of the model was 0.72 (95% CI 0.69-0.75) in the derivation cohort and 0.72 (95% CI 0.60-0.84) in the validation cohort. CONCLUSION: This model utilizing identified sociodemographic and clinical factors is predictive of AKI following HDMTX administration in adult patients with lymphoma.

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma.

INTRODUCTION: High-dose methotrexate (HDMTX)-based regimens are the treatment of choice in primary central nervous system lymphoma (PCNSL). Folinic acid (FA) rescue is used to mitigate the toxic effects of MTX on normal cells. However, the optimal dosing of FA in PCNSL remains uncertain. METHODS: We analyzed the relationship between FA dosing and treatment efficacy and toxicity in a cohort of 36 PCNSL patients treated at our institute between the years 2014 and 2022. A combination of univariate and multivariate analyses using known prognostic factors were used to determine the association between FA dosing and treatment outcomes. RESULTS: We found that higher per-treatment cumulative FA doses were associated with inferior progression-free survival (PFS), with a hazard ratio (HR) of 2.2 for each 100 mg/m2 increase in FA dose. We identified a threshold of 350 mg/m2/treatment, above which there was a significant reduction in PFS. Notably, lower FA doses did not result in increased toxicity. CONCLUSION: Our findings suggest that optimizing FA dosing to avoid very high rescue doses may improve treatment outcomes in PCNSL patients receiving HDMTX. Further prospective studies are warranted to validate these findings.

Bibliometric analysis of research trends and topic areas in traditional Chinese medicine therapy for lymphoma.

CONTEXT: Traditional Chinese Medicine (TCM) is effective as a cancer treatment modality. However, this is the first bibliometric analysis of TCM in lymphoma treatment. OBJECTIVE: This study explores the current trends and research topics of TCM in treating lymphoma from 2000 to 2023. MATERIALS AND METHODS: We searched within the Web of Science Core Collection (WoSCC) for publications on TCM in lymphoma treatment, spanning 2000 to 2023. Subsequently, we employed a comprehensive approach utilizing CiteSpace software and VOSviewer to visually analyze research trends, authors, institutions, co-cited references, and keywords. RESULTS: From January 1, 2000, to August 31, 2023, annual scientific publications on TCM for lymphoma treatment have steadily increased. Among the leading institutions in this field, the Beijing University of Chinese Medicine and the Fujian Medical University occupied the top positions. Regarding the authors, Jun Peng, Jiumao Lin, and Hongwei Chen emerged as the top three contributors. In the co-citation analysis of references, the top three co-cited references were authored by Hanahan D, Elmore S, and Livak KJ with citations numbered 13, 14, and 17, respectively. In particular, keywords reflecting current emerging trends included 'pathway', 'traditional Chinese medicine', 'oxidative stress', and 'macrophage polarization'. DISCUSSION AND CONCLUSIONS: This bibliometric analysis provides a comprehensive overview of TCM for lymphoma treatment. This analysis identified the predominant trends and research topics in the field. The findings are expected to be of significant value for researchers who focus on TCM in lymphoma treatment, helping them better understand the development of this field.

Association of MTHFR Polymorphisms With Leukoencephalopathy Risk in Patients With Primary CNS Lymphoma Treated With Methotrexate-Based Regimens.

OBJECTIVES: The folate antagonist high-dose methotrexate (HD-MTX) is integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with leukoencephalopathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in intracellular folate depletion. We assessed whether MTHFR polymorphisms affect the risk of leukoencephalopathy. METHODS: We retrospectively searched our database at the Massachusetts General Hospital for newly diagnosed PCNSL treated with HD-MTX (without radiotherapy nor intrathecal chemotherapy). RESULTS: Among 68 patients with PCNSL, MTHFR polymorphisms were found in 60 individuals (88.2%) including a 677C→T genotype, a 1298A→C genotype, or a combined 677C→T/1298A→C genotype. Neither MTX clearance nor response to induction therapy was affected by specific genotypes, and complete response was achieved in 72.1% of patients by HD-MTX-based induction. However, the 1298A→C genotype was associated with increased frequency and severity of leukoencephalopathy over time (odds ratio 4.0, CI 1.5-11.4). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0% and a specificity of 62.2% (area under the curve 0.67, CI 0.5-0.8; p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was lower for the 1298A→C genotype. DISCUSSION: The MTHFR 1298A→C genotype may serve to identify patients with PCNSL at elevated risk of HD-MTX-induced leukoencephalopathy. This seems to translate into reduced survival, potentially due to decreased functional status.

The nutritional impact of CD19-targeted CAR-T therapy versus BEAM chemotherapy for adult patients with lymphoma.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapy demonstrating durable remissions in patients with refractory or relapsing non-Hodgkin's B-cell lymphoma. Maintaining a patient's nutritional status has been demonstrated to improve outcomes in cancer treatment. However, no studies have investigated how CAR-T therapy affects nutritional status, nor compared its impact with other cancer treatments for this patient group. The primary aim of the present study was to investigate the effect of CAR-T therapy on the prevalence of nutrition impact symptoms (NIS) and nutritional status within 30 days post-treatment of patients with lymphoma compared to a conditioning regimen for autologous haematopoetic stem cell transplant (carmustine/BCNU, Etoposide, cytarabine/Ara-C, Melphalan [BEAM] auto-haematopoetic stem cell transplant [HSCT]). METHODS: Clinical notes of patients with lymphoma who underwent either CAR-T therapy or BEAM auto-HSCT between 2018 and 2021 were reviewed. Data extracted included body weight measurements and NIS, including decreased appetite, nausea, vomiting, diarrhoea, constipation, mucositis, cytokine release syndrome (CRS) and neurotoxicity at baseline and 30 ± 7 days post-treatment. RESULTS: In total, 129 adults with lymphoma (n = 88 CAR-T vs. n = 41 BEAM) were included. Nutritional status was assessed in both groups at baseline prior to treatment. Mean absolute weight change was significantly different between groups (3.05 kg in CAR-T, -5.9 kg in BEAM, p ≤ 0.001). This was also significant when weight loss was categorised into percentage weight loss (p = 0.01). CAR-T patients experienced a significantly lower prevalence of decreased appetite (52.3% vs. 97.6%) nausea (25% vs. 78%,) vomiting (10.2% vs. 53.7%), diarrhoea (43.2% vs. 96.7%) and mucositis (5.7% vs. 75.6%) combined across all levels of severity compared to BEAM chemotherapy (all p ≤ 0.01). CRS and neurotoxicity, which are specific side effects of CAR-T therapy, were moderately positively associated with weight loss. CONCLUSIONS: Weight loss, percentage weight loss and NIS were significantly reduced in CAR-T compared to BEAM treatment. However, patients who experienced neurotoxicity during treatment did have significant weight loss.

[Association of Geriatric Nutritional Risk Index with Adverse Events and Time to Treatment Failure in Malignant Lymphoma Patients Treated with(R-)EPOCH].

To date, there are no reports that examine the relationship between geriatric nutritional risk index(GNRI)at the start of chemotherapy for malignant lymphoma and adverse effects. In this study, we investigated the relationship between GNRI at the start of chemotherapy and the incidence of side effects and time to treatment failure(TTF)in(R-)EPOCH-treated patients with relapsed or refractory malignant lymphoma. A significant difference in the incidence of Grade 3 or higher thrombocytopenia was observed between high and low GNRI groups(p=0.043). The GNRI may be an indicator of hematologic toxicity in malignant lymphoma patients treated with(R-)EPOCH. There was a statistically significant difference in TTF between the high and low GNRI groups(p=0.025), suggesting that nutritional status at the start of(R-)EPOCH may affect treatment continuation.

Oxidative stress enhances the therapeutic action of a respiratory inhibitor in MYC-driven lymphoma.

MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC-overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS-010759. In a B-lymphoid cell line, ectopic MYC activity and treatment with IACS-010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro-oxidant at high doses. In these conditions, ascorbate synergized with IACS-010759 to kill MYC-overexpressing cells in vitro and reinforced its therapeutic action against human B-cell lymphoma xenografts. Hence, complex I inhibition and high-dose ascorbate might improve the outcome of patients affected by high-grade lymphomas and potentially other MYC-driven cancers.

Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor.

Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell-driven malignancies. However, approved covalent BTK inhibitors (cBTKis) are associated with treatment limitations because of off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here, we describe the preclinical profile of pirtobrutinib, a potent, highly selective, noncovalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate binding region and shows no direct interaction with C481. Consequently, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKis, prevented Y551 phosphorylation in the activation loop. These data suggest that pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines, and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed that pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest that pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical, and structural attributes with the potential to treat B-cell-driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.

Moringa oleifera L. leaf extract induces cell cycle arrest and mitochondrial apoptosis in Dalton's Lymphoma: An in vitro and in vivo study.

ETHNOPHARMACOLOGICAL RELEVANCE: The present work is based on a wide spectrum of evidences available from scientific literature which reflects nutritional and medicinal values of natural products such as plants and their extracts. Moringa oleifera is one such popular plant species amidst indigenous tribal communities which is frequently used to treat ailments such as piles, sore throat, eye and ear infections and even poisonous bites of tropical fauna such as insects or snakes. Furthermore decoction of leaf and bark was used to cure fever and cough. Evidences further reveal that Moringa oleifera L. (Family Moringaceae), is widely distributed not only over the Indian sub-continent, but also over Philippines, Central America, Saudi Arabia and the Caribbean Islands and have been traditionally used to treat cancers since ancient times. However, therapeutic effects of Moringa oleifera on Non-Hodgkin Lymphoma (NHL) are yet to be established. AIM OF THE STUDY: The study aims to investigate the anti-cancer effects of Moringa oleifera leaf extract against murine NHL Non-Hodgkin cells in vitro and in vivo. MATERIAL AND METHODS: The pharmacologically active compounds of Moringa oleifera leaf extract were identified by GC-HRMS analysis. Tests of Moringa oleifera leaf extract's cytotoxicity against DL cells were carried out using the MTT assay. Chromatin condensation along with other morphological alterations were visualized through Fluorescence microscopy. Changes in the mitochondrial membrane potential (ΔΨm), the cell cycle, and apoptosis were analysed through flow cytometer. We tried to identify proteins involved in apoptosis and cell cycle through Western blotting using BALB/c mice as a model organism. RESULTS: GC-HRMS study revealed that a methanol based leaf extract of Moringa oleifera (MOML) comprises of a variety of bioactive chemicals. Our results indicate that MOML successfully reduced the proliferation of DL cells by lowering ΔΨm, changing overall cell morphology. DL cells treated with MOML showed arrested cell cycle at the G2/M phase and substantially up-regulated the expression of p53 and p21. Elevated levels of Bax, Cyt-c, and Caspase-3 and lowered expression levels of Bcl-2 protein suggested induction of apoptosis. Mechanistically, the anticancer efficacy of MOML is attributed to MEK/ERK-mediated pathway inactivation in DL cells. It is also interesting to note that MOML-mediated inhibition of DL growth was accompanied by apoptosis induction and improvement in hematological parameters in DL-bearing mice. CONCLUSION: Our finding suggested that MOML induces apoptosis and abrogates the growth of Dalton's lymphoma both in vitro and in vivo.

In vitro and in vivo anti-lymphoma effects of Ophiorrhiza pumila extract.

BACKGROUND: Current therapeutic strategies on patients with lymphomas remains limited. Previously we found the suppressive effect of Ophiorrhiza pumila (OPE) on hepatocarcinoma. In present study, the effect of OPE on lymphoma in vitro and in vivo were investigated. METHODS: CCK-8 assay was applied to detect the effect of OPE on cell proliferation. Flow cytometry was used to analyze the effect of OPE on cell cycle distribution and apoptosis. Xenograft mouse model was conducted to determine the anti-tumor activity of OPE. TNUEL assay was performed to detect the apoptosis in tumor tissues. Western blot and immuno-histochemistry were used to determine protein expression. RESULTS: In vitro tests indicate that OPE suppressed A20 cell proliferation in a dose- and time-dependent manner. OPE treatment induced cell cycle arrest at S phase and elevated apoptosis in A20 cells. OPE displayed a significant inhibition in tumor growth in a mouse xenograft model. OPE promoted apoptosis of tumor cell in the mouse model Cleaved caspase 3 expression and Bax/Bcl2 ratio were also enhanced. In addition, OPE suppressed A20 cell viability partially by reducing phosphorylation of EGFR. CONCLUSIONS: Our data showed that OPE suppressed the proliferation of lymphoma cells and promoted apoptosis in vitro and in vivo, which might be partially mediated by inactivating EGFR signaling.

Cytotoxicity of Callerya speciosa Fractions against Myeloma and Lymphoma Cell Lines.

Callerya speciosa is widely distributed in tropical and subtropical countries and is traditionally used for preventing numerous disorders. In this study, a bioguided fractionation of ethyl acetate extract (SE) from C. speciosa root was carried out to target antioxidant and cytotoxic activities. Of the four fractions (SE1-SE4) obtained by column chromatography, SE4 had the strongest anti-radical ability in the DPPH and ABTS assays (IC50 = 0.05 and 0.17 mg/mL, respectively), with results close to butylated hydroxytoluene (BHT), a common antioxidant agent. The cytotoxic activities against the selected cells were analyzed in this study by MTT assay. Accordingly, SE2, SE3, and SE4 significantly inhibited the viability of multiple myeloma cell lines, comprising U266 (IC50 = 0.38, 0.09, and 0.11 mg/mL, respectively) and KMS11 (IC50 = 0.09, 0.17, and 0.15 mg/mL, respectively), mantle cell lymphoma Mino (IC50 = 0.08, 0.16, and 0.15 mg/mL, respectively), and the noncancerous cell line LCL (IC50 = 0.40, 0.32, and 0.21 mg/mL, respectively). At a concentration of 125 µg/mL, SE2, SE3, and SE4 induced the cell apoptosis of U266 (32.2%, 53.2%, and 55.6%, respectively), KMS11 (36.9%, 40.8%, and 47.9%, respectively), Mino (36.6%, 39.8%, and 22.0%, respectively), and LCL (12.4%, 17.5%, and 23.5%, respectively) via annexin V assay. The dominant compounds detected in fractions by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS), were identified as isoflavones. This is the first report describing C. speciosa as a promising natural source of antileukemia and antimyeloma agents, which may be useful for the development of blood cancer treatments.

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors.

PURPOSE: Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. METHODS: In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed. RESULTS: There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153). CONCLUSION: Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.

Pemetrexed for Recurrent Primary Central Nervous System Lymphoma in the Elderly: Results of a Retrospective Study.

Aim: Primary central nervous system lymphoma (PCNSL) is an aggressive, destructive, and rapidly progressive malignant brain tumor. Although aggressive therapies were studied trying to increase the median survival of PCNSL, the high relapse rate of PCNSL is still a big problem for the oncology medicine. A retrospective study was made to evaluate the efficacy and safety of pemetrexed in the treatment of patients with recurrent PCNSL. Methods: Twenty-three confirmed recurrent PCNSL patients were selected during April 2012 and August 2016. Dexamethasone, B12, and folic acid were used to produce the toxicity related to pemetrexed. The patients were intravenously given pemetrexed (900 mg/m2) every three weeks for 6 weeks. Results: After the treatment, 7 patients were in complete remission, 6 patients in partial remission, 4 patients in stable condition, and 6 patients in progression. There were 56.5% and 73.9% in the overall response rate and the disease control rate, respectively. The median overall survival (OS) was 6.6 months (95% CI, 4.6-8.6). Conclusion: This study has been the first time to evaluate the safety and effectiveness of pemetrexed on elderly recurrent PCNSL patients. Results demonstrate that using high-dose pemetrexed might be a feasible and effective treatment for recurrent PCNSL in the elderly, and clinical trials should be conducted to further confirm it.

Evaluation of the protective effects of Ganoderma applanatum against doxorubicin-induced toxicity in Dalton's Lymphoma Ascites (DLA) bearing mice.

The toxic side effects of doxorubicin in cancer treatment are well established. Here we show that methanolic extract of the fungus Ganoderma applanatum offers protection against cardio- and hepatotoxicity induced by doxorubicin (DOX) in Dalton's Lymphoma Ascites (DLA) bearing mice. Treatment of DLA mice with 20 mg/kg of doxorubicin significantly increased the activities of serum toxicity markers including aspartate amino-transferase (AST), alanine amino-transferase (ALT) and lactate dehydrogenase (LDH). However, co-administration of doxorubicin (20 mg/kg) by intraperitoneal injection and G. applanatum (150 mg/kg) by oral gavage in DLA mice lowered the AST, ALT, and LDH activities when compared to DOX alone treatment. Treatment of DLA mice with DOX alone resulted in reduced GSH contents, and decreased the activities of glutathione-s-transferase (GST), catalase (CAT), and superoxide dismutase (SOD). Treatment of DOX-administered DLA mice with G. applanatum however increased the GSH content and elevated the activities of GST, CAT, and SOD. Among the various solvent extracts of G. applanatum, methanolic extract showed the highest phenolic (376.5 ± 15.24 mg GAE/g) and flavonoid (4717.79 ± 170.22 mg quercetin/g) contents compared to the aqueous (216.3 ± 7.33 mg GAE/g) and chloroform extracts (137.27 ± 1.03 mg GAE/g). Consistently, the methanolic extract was found to possess the highest free radical scavenging activities when compared to the aqueous and chloroform extracts as measured by ABTS and DPPH assays. Our results thus suggest that the protective roles of G. applanatum in DOX-induced toxicity could be an attribute of the antioxidant properties conferred by the high phenolic and flavonoid contents.

Efficacy of Boron Neutron Capture Therapy in Primary Central Nervous System Lymphoma: In Vitro and In Vivo Evaluation.

BACKGROUND: Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation method. High-dose methotrexate and whole-brain radiation therapy (WBRT) are the recommended treatments for primary central nervous system lymphoma (PCNSL). This tumor responds well to initial treatment but relapses even after successful treatment, and the prognosis is poor as there is no safe and effective treatment for relapse. In this study, we aimed to conduct basic research to explore the possibility of using BNCT as a treatment for PCNSL. METHODS: The boron concentration in human lymphoma cells was measured. Subsequently, neutron irradiation experiments on lymphoma cells were conducted. A mouse central nervous system (CNS) lymphoma model was created to evaluate the biodistribution of boron after the administration of borono-phenylalanine as a capture agent. In the neutron irradiation study of a mouse PCNSL model, the therapeutic effect of BNCT on PCNSL was evaluated in terms of survival. RESULTS: The boron uptake capability of human lymphoma cells was sufficiently high both in vitro and in vivo. In the neutron irradiation study, the BNCT group showed a higher cell killing effect and prolonged survival compared with the control group. CONCLUSIONS: A new therapeutic approach for PCNSL is urgently required, and BNCT may be a promising treatment for PCNSL. The results of this study, including those of neutron irradiation, suggest success in the conduct of future clinical trials to explore the possibility of BNCT as a new treatment option for PCNSL.

Myricetin exhibit selective anti-lymphoma activity by targeting BTK and is effective via oral administration in vivo.

BACKGROUND: Myricetin (MYR) is a polyhydroxy flavone originally isolated from Myrica rubra, and is widely distributed in a variety of medicinal plants and delicious food. MYR has been proven to have inhibitory effects against various types of cancer. However, the exact role of MYR in lymphoma development is still unclear. METHODS: In vitro, the MTT assay was performed to evaluate the activity of human diffuse large B lymphoma cell TMD-8 and other tumor cells. Homogeneous time-resolved fluorescence (HTRF) and molecular docking were used to detect the target of MYR inhibiting TMD-8 cells. In addition, flow cytometry, Annexin V-FITC/PI assays, Hoechst 33258, and mondansylcadaverine (MDC) fluorescent standing were used to detect the cell cycle, apoptosis, and autophagy, respectively. Moreover, Western blot analysis was conducted to analyze related signaling pathways. In TMD-8 cell xenotransplanted mice, immunohistochemistry, histopathology, and blood biochemical tests were used to evaluate the effectiveness and safety of oral administration of MYR. RESULTS: Here, we found that MYR is more sensitive to TMD-8 cells than other tumor cells by targeting bruton tyrosine kinase (BTK). BTK is an attractive target for the treatment of B-cell malignancies. The HTRF assay showed that MYR inhibited BTK kinase with an IC50 of 1.82 µM. Furthermore, the HTRF assay and Western blot analysis demonstrated that MYR could bind to key residues (Ala478, Leu408, Thr474) in the BTK active pocket, inhibit the autophosphorylation on tyrosine 223, and block BTK/ERK and BTK/AKT signal transduction cascades (including downstream substrates GSK-3ß, IKK, STAT3, and NF-κb). The results of cell cycle, apoptosis, and autophagy showed that MYR could induce G1/G0 cycle arrest by regulating cyclinB1/D1 expression, induce apoptosis by increasing the Bax/Bcl-2 ratio, and trigger autophagy by inhibiting mTOR activation. In vivo, oral administration of MYR significantly inhibited the growth of TMD-8 xenograft tumora without toxic side effects. Furthermore, Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis showed that MYR could inhibit proliferation and induce apoptosis of tissue lymphoma cells. CONCLUSION: Taken together, MYR is an oral available natural BTK inhibitor that effectively inhibits the growth of lymphoma TMD-8 cells both in vitro and in vivo. In addition, our findings support that the use of MYR is a novel and promising therapeutic strategy for the treatment of lymphoma.

Curcumin in combination with homoharringtonine suppresses lymphoma cell growth by inhibiting the TGF-ß/Smad3 signaling pathway.

Both homoharringtonine (HHT) and curcumin exhibit anti-proliferative effects on lymphoma cells, but the effects of combined HHT and curcumin treatment remain unclear. Here, we investigated the effects of HHT/curcumin combination on the proliferation, apoptosis, and invasion in lymphoma cells. CCK-8, flow cytometry, and transwell assays were used to assess proliferation, apoptosis, and invasion of U937 and Raji cells. p-Smad3, E-cadherin, and N-cadherin expression were also measured in Raji cells using Western blot assays. Combination of HHT and curcumin synergistically inhibited U937 and Raji cell proliferation and invasion. In addition, the combination treatment markedly increased apoptosis of Raji cells as evidenced by increased Bax, cleaved caspase 3, and cleaved caspase 9 expression. Meanwhile, the combination treatment promoted anti-tumor mechanisms in Raji cells as indicated by decreases in p-Smad3 and N-cadherin and increases in E-cadherin. In vivo experiments showed that the combination treatment suppressed tumor growth in a mouse Raji xenograft model. Our findings indicate that combination of HHT and curcumin inhibited lymphoma cell growth by downregulating the TGF-ß/Smad3 pathway. These results suggest that HHT combined with curcumin might be a promising therapeutic approach for the treatment of lymphoma.

Pros and Cons of the Cannabinoid System in Cancer: Focus on Hematological Malignancies.

The endocannabinoid system (ECS) is a composite cell-signaling system that allows endogenous cannabinoid ligands to control cell functions through the interaction with cannabinoid receptors. Modifications of the ECS might contribute to the pathogenesis of different diseases, including cancers. However, the use of these compounds as antitumor agents remains debatable. Pre-clinical experimental studies have shown that cannabinoids (CBs) might be effective for the treatment of hematological malignancies, such as leukemia and lymphoma. Specifically, CBs may activate programmed cell death mechanisms, thus blocking cancer cell growth, and may modulate both autophagy and angiogenesis. Therefore, CBs may have significant anti-tumor effects in hematologic diseases and may synergistically act with chemotherapeutic agents, possibly also reducing chemoresistance. Moreover, targeting ECS might be considered as a novel approach for the management of graft versus host disease, thus reducing some symptoms such as anorexia, cachexia, fatigue, anxiety, depression, and neuropathic pain. The aim of the present review is to collect the state of the art of CBs effects on hematological tumors, thus focusing on the essential topics that might be useful before moving into the clinical practice.

Anticancer and Anti-inflammatory Effect of Diosmin against Dalton Ascitic Lymphoma Induced Leukemia.

Cancer is the world's biggest health problem and cancer-induced mortality happened all over the planet after the heart disease. The present study was to scrutinize the anti-leukemia effect of diosmin against Dalton Ascitic Lymphoma (DAL) induced leukemia in mice. DAL cell was used for induction the solid tumor. Body weight, life spans, tumor volume and mean survival time was estimated. Antioxidant, biochemical and pro-inflammatory cytokines were estimated. Diosmin showed the cell viability effect at dose dependent manner against the both cell lines. DAL induced solid tumor mice showed the decreased body weight, mean survival days, non viable cell count and increased the tumor volume, viable cell count and diosmin significantly (p < 0.001) reverse the effect of DAL. Diosmin significantly (p < 0.001) altered the hematological, differential leukocytes, antioxidant, biochemical, pro-inflammatory cytokines at dose dependently. Collectively, we can say that diosmin might alter the DAL induced abnormality via antioxidant and anti-inflammatory effects.