scholarly journals Impact of Qi-Invigorating Traditional Chinese Medicines on Diffuse Large B Cell Lymphoma Based on Network Pharmacology and Experimental Validation

2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Huang ◽  
Jinkun Lin ◽  
Surong Huang ◽  
Jianzhen Shen
Keyword(s):  
Molecular Docking ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Network Pharmacology ◽  
Active Ingredients ◽  
Hub Genes ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Background: It has been verified that deficiency of Qi, a fundamental substance supporting daily activities according to the Traditional Chinese Medicine theory, is an important symptom of cancer. Qi-invigorating herbs can inhibit cancer development through promoting apoptosis and improving cancer microenvironment. In this study, we explored the potential mechanisms of Qi-invigorating herbs in diffuse large B cell lymphoma (DLBCL) through network pharmacology and in vitro experiment.Methods: Active ingredients of Qi-invigorating herbs were predicted from the Traditional Chinese Medicine Systems Pharmacology Database. Potential targets were obtained via the SwissTargetPrediction and STITCH databases. Target genes of DLBCL were obtained through the PubMed, the gene-disease associations and the Malacards databases. Overlapping genes between DLBCL and each Qi-invigorating herb were collected. Hub genes were subsequently screened via Cytoscape. The Gene Ontology and pathway enrichment analyses were performed using the DAVID database. Molecular docking was performed among active ingredients and hub genes. Hub genes linked with survival and tumor microenvironment were analyzed through the GEPIA 2.0 and TIMER 2.0 databases, respectively. Additionally, in vitro experiment was performed to verify the roles of common hub genes.Results: Through data mining, 14, 4, 22, 22, 35, 2, 36 genes were filtered as targets of Ginseng Radix et Rhizoma, Panacis Quinquefolii Radix, Codonopsis Radix, Pseudostellariae Radix, Astragali Radix, Dioscoreae Rhizoma, Glycyrrhizae Radix et Rhizoma for DLBCL treatment, respectively. Then besides Panacis Quinquefolii Radix and Dioscoreae Rhizoma, 1,14, 10, 14,13 hub genes were selected, respectively. Molecular docking studies indicated that active ingredients could stably bind to the pockets of hub proteins. CASP3, CDK1, AKT1 and MAPK3 were predicted as common hub genes. However, through experimental verification, only CASP3 was considered as the common target of Qi-invigorating herbs on DLBCL apoptosis. Furthermore, the TIMER2.0 database showed that Qi-invigorating herbs might act on DLBCL microenvironment through their target genes. Tumor-associated neutrophils may be main target cells of DLBCL treated by Qi-invigorating herbs.Conclusion: Our results support the effects of Qi-invigorating herbs on DLBCL. Hub genes and immune infiltrating cells provided the molecular basis for each Qi-invigorating herb acting on DLBCL.

scholarly journals Circulating Exosomal MiR-107 Restrains Tumorigenesis in Diffuse Large B-Cell Lymphoma by Targeting 14-3-3η

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiarui Liu ◽  
Yang Han ◽  
Shunfeng Hu ◽  
Yiqing Cai ◽  
Juan Yang ◽  
...  
Keyword(s):  
B Cell ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prognostic Indicator ◽  
Diagnostic Value ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Exosomes, nanometer-sized membranous vesicles in body fluids, have emerged as promising non-invasive biomarkers for cancer diagnosis. However, the function of exosomes in diffuse large B-cell lymphoma (DLBCL) remains elusive. This study aimed to investigate the role of exosomal miR-107 in lymphomagenesis and explore its clinical significance. In this study, decreased exosomal miR-107, miR-375-3p, and upregulated exosomal miR-485-3p were detected in the plasma of DLBCL patients and showed potential diagnostic value. Downregulated miR-107 expression was associated with advanced Ann Arbor stage, high IPI score, LDH, and β2-MG level in DLBCL patients. Overexpression of miR-107 by miR-107 Agomir significantly abrogated cell proliferation, induced apoptosis, and inhibited cell invasion in vitro, and repressed tumor growth in vivo. Moreover, the downregulation of miR-107 went in the opposite direction. The target genes of miR-107 were mainly enriched in the PI3K-Akt, Hippo, and AMPK signaling pathways. Notably, upregulated 14-3-3η (YWHAH) was suppressed by miR-107 in DLBCL, suggesting that miR-107 may restrain tumorigenesis by targeting 14-3-3η. In summary, this study unveils the function of miR-107 in lymphomagenesis, highlighting its potential as a diagnostic and prognostic indicator and as a new therapeutic target in the management of DLBCL.

An Orally Available Small Molecule BCL6 Inhibitor Effectively Suppresses Diffuse Large B Cell Lymphoma Cells Growth in Vitro and in Vivo

2021 ◽  
Author(s):  
Yajing Xing ◽  
Weikai Guo ◽  
Min Wu ◽  
Jiuqing Xie ◽  
Dongxia Huang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Small Molecule ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: The transcription factor B cell lymphoma 6 (BCL6) is an oncogenic driver of diffuse large B cell lymphoma (DLBCL) and mediates lymphomagenesis through transcriptional repression of its target genes by recruiting corepressors to its N-terminal broad-complex/tramtrack/bric-a-brac (BTB) domain. Blocking the protein-protein interactions of BCL6 and its corepressors has been proposed as an effective approach for the treatment of DLBCL. However, BCL6 inhibitors with excellent drug-like properties are rare. Hence, the development of BCL6 inhibitors is worth pursuing. Methods: We screened our internal chemical library by luciferase reporter assay and Homogenous Time Resolved Fluorescence (HTRF) assay and a small molecule compound named WK500B was identified. The binding affinity between WK500B and BCL6 was evaluated by surface plasmon resonance (SPR) assay and the binding mode of WK500B and BCL6 was predicted by molecular docking. The function evaluation and anti-cancer activity of WK500B in vitro and in vivo was detected by immunofluorescence assay, Real-Time Quantitative PCR, cell proliferation assay, cell cycle assay, cell apoptosis assay, enzyme-linked immunosorbent assay (ELISA), germinal centre (GC) formation mouse model and mouse xenograft model. Results: WK500B engaged BCL6 inside cells, blocked BCL6 repression complexes, reactivated BCL6 target genes, killed DLBCL cells and caused apoptosis as well as cell cycle arrest. In animal models, WK500B inhibited germinal centre formation and DLBCL tumor growth without toxic and side effects. Moreover, WK500B showed favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors. Conclusions: WK500B showed strong efficacy and favourable pharmacokinetics and presented superior druggability compared to other BCL6 inhibitors. So, WK500B is a promising candidate that could be developed as an effective orally available therapeutic agent for DLBCL.

Novel cyclophosphamide of natural products osalmide and pterostilbene induces cytotoxicity and cell cycle arrest in diffuse large B-cell lymphoma cells

2020 ◽  
Vol 52 (4) ◽  
pp. 401-410
Author(s):  
Mengyu Xi ◽  
Wan He ◽  
Bo Li ◽  
Jinfeng Zhou ◽  
Zhijian Xu ◽  
...  
Keyword(s):  
Natural Products ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Underlying Mechanism ◽  
Anticancer Activities ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common category and disease entity of non-Hodgkin lymphoma. Osalmide and pterostilbene are natural products with anticancer activities via different mechanism. In this study, using a new synthetic strategy for the two natural products, we obtained the compound DCZ0801, which was previously found to have anti-multiple myeloma activity. We performed both in vitro and in vivo assays to investigate its bioactivity and explore its underlying mechanism against DLBCL cells. The results showed that DCZ0801 treatment gave rise to a dose- and time-dependent inhibition of cell viability as determined by CCK-8 assay and flow cytometry assay. Western blot analysis results showed that the expression of caspase-3, caspase-8, caspase-9 and Bax was increased, while BCL-2 and BCL-XL levels were decreased, which suggested that DCZ0801 inhibited cell proliferation and promoted intrinsic apoptosis. In addition, DCZ0801 induced G0/G1 phase arrest by downregulating the protein expression levels of CDK4, CDK6 and cyclin D1. Furthermore, DCZ0801 exerted an anti-tumor effect by down-regulating the expressions of p-PI3K and p-AKT. There also existed a trend that the expression of p-JNK and p-P38 was restrained. Intraperitoneal injection of DCZ0801 suppressed tumor development in xenograft mouse models. The preliminary metabolic study showed that DCZ0801 displayed a rapid metabolism within 30 min. These results demonstrated that DCZ0801 may be a new potential anti-DLBCL agent in DLBCL therapy.

scholarly journals Repurposing dasatinib for diffuse large B cell lymphoma

2019 ◽  
Vol 116 (34) ◽  
pp. 16981-16986 ◽  
Author(s):  
Claudio Scuoppo ◽  
Jiguang Wang ◽  
Mirjana Persaud ◽  
Sandeep K. Mittan ◽  
Katia Basso ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Multikinase Inhibitor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.

Abstract B38: FOXP1 truncated isoforms differentially regulate target genes in diffuse large B cell lymphoma.

2013 ◽  
Author(s):  
Emily Camilleri ◽  
Carlos Aya-Bonilla ◽  
Jamie Nourse ◽  
Philip J. Brown ◽  
Alison H. Banham ◽  
...  
Keyword(s):  
B Cell ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Truncated Isoforms ◽  
Large B Cell

Array CGH Analysis for Target Genes at 6p21 Amplification Region in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1116-1116
Author(s):  
Yumiko Kasugai ◽  
Hiroyuki Tagawa ◽  
Yoshihiro Kameoka ◽  
Sivasundaram Karnan ◽  
Ritsuro Suzuki ◽  
...  
Keyword(s):  
B Cell ◽  
Target Genes ◽  
Array Cgh ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cyclin D3 ◽  
Common Region ◽  
Bac Clones ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Amplification of 6p21 has been detected in various solid tumor and hematological neoplasms. These include hepatoma, osteosarcoma, pancreatic cancer, bladder cancer, and mantle cell lymphoma . However, no candidate target genes in this amplified region have been identified. In diffuse large B-cell lymphoma (DLBCL), no amplification has been reported. Recently, we established genome-wide array comparative genomic hybridization (array CGH) consisting of 2300 BAC clones that can survey a whole genome at the density of an average size of 1.3 Mb. The array CGH detected amplification at 6p21 in 12 of 70 (24%) DLBCL patients (Tagawa et al., Cancer Res. in press) and one DLBCL cell line, SUDHL-9. We next made high density array glass for 6p21 region with 23 BAC clones covering 3 Mb. We found that the minimal common region of amplification was approximately 2Mb in size. In this region, there are 27 known genes including cyclin D3. The cyclin D3 has been reported to be overexpressed in a case of DLBCL with t(6;14)(p21.1;q32.3). We have analyzed expression level of those genes in the minimal common region of amplification, and found that five genes, BYSL, cyclin D3, TBN, KIAA0240, and TBCC were overexpressed. These results indicate that not only cyclin D3 but also other genes are also possible target genes for the 6p21 amplification.

Signatures of Response to the Proteasome Inhibitor Bortezomib in Diffuse Large B-Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 608-608
Author(s):  
Friedrich Feuerhake ◽  
Stefano Monti ◽  
Jonathan Blank ◽  
Erxi Wu ◽  
Wen Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Target Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Rank Test ◽  
Bortezomib Treatment ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract The proteasome inhibitor, bortezomib (VELCADE®, formerly PS341), has significant anti-tumor activity in several lymphoid malignancies. Reported targets of this broad-based inhibitor include the NF K B pathway (I K B A). Recently defined subtypes of large B-cell lymphoma (LBCL) exhibit constitutive activation of NF K B, prompting us to analyze the efficacy of bortezomib in a panel of 10 DLBCL cell lines. Six of the diffuse LBCL cell lines were sensitive to bortezomib treatment at doses below 10 nM (range IC50 = 2.9 to 6.9 nM) whereas 4 cell lines were resistant at 10 nM (IC50 = 14.8 to 70.2 nM). Baseline proteasomal function, as defined by cleavage of the 20S proteasome-specific fluorogenic peptide LLVY-AMC, was similar in sensitive and resistant DLBCLs; however, the IC50 for bortezomib proteasomal inhibition was somewhat lower in sensitive vs. resistant lines (sens. vs res., p = .04, one-sided t test). Baseline NF K B activity varied widely in the DLBCL cell lines and did not differ in cell lines that were sensitive vs. resistant to bortezomib. Ten nM bortezomib did not inhibit NF K B activity in resistant DLBCL cell lines whereas the same dose reduced NF K B activity in sensitive DLBCL cell lines (sens. vs. res., p < .005, rank test [Mann-Whitney]). However, 5 of 6 sensitive DLBCL cell lines had very low baseline NF K B levels (< 0.5 relative absorbance units) suggesting that NF K B inhibition was not a major factor in bortezomib response and prompting further analysis of additional bortezomib targets. Three sensitive and 1 resistant DLBCL cell line were selected for detailed analyses of transcriptional profiles following bortezomib treatment. We developed an algorithm for identifying genes that were significantly up- or down-regulated in the bortezomib-sensitive cell lines but unchanged in the resistant line. In addition, we utilized gene set enrichment analysis (GSEA) and gene ontogeny (GO) termed enrichment to interpret the molecular signatures of response. Genes down-regulated in response to bortezomib included critical B-cell transcription factors, components of the B-cell receptor signaling cascade and genes regulating mitosis and cell cycle control; up-regulated genes included heat shock proteins (HSP) and multiple proteasomal components. Consistent with the functional data, down-regulation of NF K B target genes was not a common feature in all bortezomib-sensitive cell lines. In contrast, target genes of the c-MYC transcription factor were significantly down-regulated and c-MYC activity was decreased in sensitive (but not resistant) DLBCL cell lines following bortezomib treatment (sens. vs. res., p < .005, rank test). Taken together, the results provide insights into likely mechanisms of action of bortezomib in DLBCL, highlighting c-MYC as a potentially important target and identifying HSP as a complementary target to overcome bortezomib resistance.

HCD122, an Antagonist Human Anti-CD40 Monoclonal Antibody, Enhances Efficacy of CHOP in Tumor Xenograft Model of Human Diffuse Large B-Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 528-528 ◽  
Author(s):  
Mohammad Luqman ◽  
Ssucheng J. Hsu ◽  
Matthew Ericson ◽  
Sha Klabunde ◽  
Seema Kantak
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Tumor Growth ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract HCD122 (formerly known as CHIR-12.12), is a fully human anti-CD40 monoclonal antibody (mAb) currently in Phase I clinical trials for treatment of chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). An IgG1 antibody selected for its potency as an antagonist of the CD40 signaling pathway, HCD122 both inhibits CD40/CD40L-stimulated growth of lymphoma cells ex vivo, and mediates highly effective Antibody Dependent Cell-mediated Cytotoxicity (ADCC) in vitro. As a single agent, HCD122 exhibits potent anti-tumor activity in vivo, in preclinical models of MM, Hodgkin’s lymphoma, Burkitt’s lymphoma, mantle cell lymphoma and diffused large B-cell lymphoma (DLBCL). Although several therapeutic antibodies approved for treatment of Non-Hodgkin’s Lymphoma have clinical activity as single agents, combining these antibodies with standard-of-care chemotherapeutic regimens such as CHOP (cytoxan, vincristine, doxorubicin and prednisone) is proving optimal for both increasing response rates and extending survival, and antibodies currently in clinical development are likely to be used in combination therapies in the future. Therefore the studies reported here examine the effects of combining HCD122 with CHOP, the standard for treatment of high grade NHL, in in vitro and in vivo models of DLBCL. In the xenograft RL model of DLBCL, HCD122 administered intraperitoneally weekly at 1 mg/kg as a single agent, or in combination with CHOP (H-CHOP), and CHOP alone all significantly reduced tumor growth at day 25 when compared to treatment with huIgG1 control antibody (P<0.001). However, tumor growth delay (time to reach tumor size of 500 mm3) was significantly longer for H-CHOP (17.5 days), than for CHOP (8 days) or HCD122 (6 days) (p < 0.001). No toxicity was observed with the H-CHOP combination. Interestingly, at the end of the study (day 35), reduction in tumor growth was significantly greater in the treatment group that received H-CHOP than the groups that received either 10 mg/kg Rituxan plus CHOP (R-CHOP) (p < 0.05) or CHOP alone (p < 0.001). These data show that in this model, treatment with the combination H-CHOP results in greater anti-tumor efficacy than with either modality alone or R-CHOP. We have observed that in vitro, exposure to CD40 Ligand (CD40L) results in aggregation of DLBCL cells, and postulate that interfering with the ability of cancer cells to adhere and interact with each other and their microenvironment may potentiate the effect of chemotherapeutics. To elucidate the mechanism by which the combination of HCD122 and CHOP enhanced efficacy in vivo, we developed an in vitro system to examine the effects of HCD122 on the expression of adhesion molecules in the RL and SU-DHL-4 cell lines. In these studies, HCD122 inhibited CD40L-induced expression of CD54, CD86 and CD95 in both cell lines, as well as aggregation of SU-DHL-4 cells. The combined effect of each of the components of CHOP with HCD122 in three-dimensional spheroid cultures is currently under investigation. These data provide a therapeutic rationale for combination of HCD122 with CHOP in DLBCL clinical trials.

Loss of IRF8 Inhibits the Growth of Diffuse Large B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3004-3004
Author(s):  
Yulian Xu ◽  
Lei Jiang ◽  
Rachel R. Fang ◽  
Jeff Xiwu Zhou ◽  
Herbert Morse
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Cell Lymphoma ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Expression Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract IRF8 is a transcription factor with a critical role in B lymphocyte development and biological functions. Although it has been reported that IRF8 is highly expressed in human diffuse large B-cell lymphoma (DLBCL) and the translocation of IRF8-IgH loci occurs in DLBCL, little information is available regarding the function and mechanisms for the role of IRF8 in DLBCL. In this study, by using several human DLBCL cell lines with shRNA-mediated decrease in IRF8 expression levels, we found that the loss of IRF8 significantly reduced the proliferation of lymphoma cells (Figure 1). Mechanistically, decreasing the levels of IRF8 led to a decrease in p38 and ERK phosphorylation (Figure 2), molecular events critical for B cell proliferation. Furthermore, using a xenograft lymphoma mice model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (n=5 for each group) (Figure 3). Analysis of public available data also suggested that the expression levels of IRF8 mRNA in human DLBCL tissues were inversely correlated patientsÕ overall survival time. Taken together, this study showed that IRF8 may play an oncogenic role in human DLBCL by promoting cell proliferation. Figure 1. Loss of IRF8 decreased the proliferation of DLBCL cells in vitro. Figure 1. Loss of IRF8 decreased the proliferation of DLBCL cells in vitro. Figure 2. Loss of IRF8 decreased the phosphorylation of p38 and ERK in DLBCL cells. Figure 2. Loss of IRF8 decreased the phosphorylation of p38 and ERK in DLBCL cells. Figure 3. Loss of IRF8 decreased the growth of DLBCL in vivo. Figure 3. Loss of IRF8 decreased the growth of DLBCL in vivo. Disclosures No relevant conflicts of interest to declare.

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