Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunochemotherapies have improved outcomes in indolent lymphoma. However, response durations progressively shorten following each treatment, and the majority of patients eventually die from the disease. Thus, new, less toxic, and more active treatments are needed. Protein kinase C (PKC), which has been repeatedly implicated in B-cell lymphoma progression, may be a new target for lymphoma cell growth inhibition. Enzastaurin, a PKC-beta inhibitor, has toxic effects on a variety of cancer cells. The purpose of the present study was to assess the antitumor activity of enzastaurin on B-cell lymphoma cell lines and to investigate the underlying antitumor mechanisms. Enzastaurin induced apoptosis and inhibited phosphorylation of PKC, RSK, AKT, and downstream proteins. Moreover, our results reveal a new mechanism for enzastaurin-induced apoptosis via BAD activation. Finally, enzastaurin synergizes in its effects with chlorambucil and fludarabine, respectively. Taken together, our results strongly support clinical evaluation of enzastaurin in patients with B-cell lymphoma.
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PMID:Effects of enzastaurin, alone or in combination, on signaling pathway controlling growth and survival of B-cell lymphoma cell lines. 2021 11

Interactions between histone deacetylase inhibitors (HDACIs) and the novel proteasome inhibitor carfilzomib (CFZ) were investigated in GC- and activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells. Coadministration of subtoxic or minimally toxic concentrations of CFZ) with marginally lethal concentrations of HDACIs (vorinostat, SNDX-275, or SBHA) synergistically increased mitochondrial injury, caspase activation, and apoptosis in both GC- and ABC-DLBCL cells. These events were associated with Jun NH2-terminal kinase (JNK) and p38MAPK activation, abrogation of HDACI-mediated nuclear factor-kappaB activation, AKT inactivation, Ku70 acetylation, and induction of gammaH2A.X. Genetic or pharmacologic JNK inhibition significantly diminished CFZ/vorinostat lethality. CFZ/vorinostat induced pronounced lethality in 3 primary DLBCL specimens but minimally affected normal CD34(+) hematopoietic cells. Bortezomib-resistant GC (SUDHL16) and ABC (OCI-LY10) cells exhibited partial cross-resistance to CFZ. However, CFZ/vorinostat dramatically induced resistant cell apoptosis, accompanied by increased JNK activation and gammaH2A.X expression. Finally, subeffective vorinostat doses markedly increased CFZ-mediated tumor growth suppression and apoptosis in a murine xenograft OCI-LY10 model. These findings indicate that HDACIs increase CFZ activity in GC- and ABC-DLBCL cells sensitive or resistant to bortezomib through a JNK-dependent mechanism in association with DNA damage and inhibition of nuclear factor-kappaB activation. Together, they support further investigation of strategies combining CFZ and HDACIs in DLBCL.
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PMID:The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. 3112 19

Neoplastic cells rely on key oncogenic pathways for their gain of proliferative and/or loss of apoptotic potential. Therapy targeted at specific points in these pathways has the potential to eliminate cancer cells by inducing differentiation or apoptosis. Concurrent immunophenotypic evaluation of survival pathways in nodular sclerosing classical Hodgkin lymphoma (cHL-NS) tissues has not previously been undertaken. We took the tissue microarray (TMA)-based approach to retrospectively evaluate the activation state of key oncogenic pathways by immunohisto-chemistry (IHC) in a series of 6 cases of cHL-NS (with predominantly syncitial areas). For comparison, 2 cases of diffuse large B-cell lymphoma (DLBCL), and 1 case of follicular hyperplasia (FH) were included in the study. Infiltration of T regulatory cells (Tregs) in the tumor microenvironment was assessed by expression of the Foxp3 transcription factor. Differential upregulation of the mitogen-activated protein kinase (MAPK)-extracellular signal related kinase (ERK), signal transducers and activators of transcription (STAT)3, and protein kinase c - alpha (PKC-alpha) pathways was seen among the cHL cases, whereas nuclear factor - kappa B (NF-kB) and phosphoinositide 3 kinase (PI3 K)-AKT-mammalian target of rapamycin (mTOR) pathways were equally activated in the neoplastic Reed-Sternberg cells of the 6 cHL-NS cases. Marked difference in the morphoproteomic profile was seen amongst the two cases of DLBCL. The amount of Foxp3+ T regulatory cells (Tregs) in the tumor microenvironment was highly variable ranging from 6/hpf to 120/hpf in cHL-NS, and 1/hpf to 82/hpf in DLBCL. In this pilot study, concurrent evaluation of oncogenic pathways in cHL-NS and DLBCL offers powerful insights in the putative therapeutic targets for an individualized approach to diagnosis and therapy.
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PMID:Tissue-microarray based immunohistochemical analysis of survival pathways in nodular sclerosing classical Hodgkin lymphoma as compared with Non-Hodgkin's lymphoma. 2036 41

Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of fatty acids, has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we investigated the role of FASN in a large series of DLBCL tissues in a tissue microarray (TMA) format followed by in vitro studies using DLBCL cell lines. FASN was found to be expressed in 62.6% DLBCL samples and was seen in highly proliferative tumors, manifested by high Ki67 (P < 0.0001). Significant association was found between tumors expressing high FASN and c-Met tyrosine kinase (P < 0.0002), as well as p-AKT (P = 0.0309). In vitro, pharmacological FASN inhibition and small interference RNA (siRNA) targeted against FASN triggered caspase-dependent apoptosis and suppressed expression of c-Met kinase in DLBCL cell lines, which further highlighted the molecular link between FASN and c-Met kinase. Finally, simultaneous targeting of FASN and c-Met with specific chemical inhibitors induced a synergistically stimulated apoptotic response in DLBCL cell lines. These findings provide evidence that FASN, via c-Met tyrosine kinase, plays a critical role in the carcinogenesis of DLBCL and strongly suggest that targeting FASN may have therapeutic value in treatment of DLBCL.
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PMID:Inhibition of fatty acid synthase suppresses c-Met receptor kinase and induces apoptosis in diffuse large B-cell lymphoma. 2042 96

We investigated the role of the leptin receptor (Ob-R) and its relationship with PI3K/AKT activation in diffuse large B-cell lymphoma (DLBCL) clinical samples followed by in vitro studies using a panel of CRC cell lines. Leptin exerts its physiological action through its receptor Ob-R. Overexpression of Ob-R has been implicated in the pathogenesis of a variety of malignancies; however, its role in DLBCL has not been investigated. Using immunohistochemistry on a large cohort of DLBCL samples in a tissue microarray format, Ob-R immunostaining was detected in 86/216 (39.8%). Ob-R overexpression was associated with the catalytic subunit p110 of PI3K (p = 0.0283), activated AKT (p = 0.0003), and antiapoptotic marker XIAP (p = 0.0008) expression. In in vitro analysis using DLBCL cell lines, our data showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of the PI3K/AKT signaling pathway. Pretreatment of DLBCL cells with Ob-R specific small interference RNA or inactivation of PI3K/AKT activity by LY294002 abolished these responses. Altogether, these data suggest that leptin plays a critical role in DLBCL pathogesis through the P13K/AKT pathway via Ob-R.
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PMID:Leptin receptor expression and its association with PI3K/AKT signaling pathway in diffuse large B-cell lymphoma. 2044 80

Hepatocyte growth factor/c-MET has emerged as a potential therapeutic target for several cancers; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been fully elucidated. In this study, we first investigated the role of c-Met in a large series of DLBCL tissues in a tissue microarray format. We then followed this with in vitro studies on DLBCL cell lines using either pharmacological inhibitors of c-Met or siRNA knockdown strategy. c-Met was found to be overexpressed in 73.2% of patients (186/254) and was significantly associated with overexpression of p-AKT (P=0.0274), p-GSK3 (P=0.0047) and Ki-67 (P=0.0012). Interestingly, c-Met overexpression was significantly more common in the germinal center subtype of DLBCL, as compared with activated B cell subtype (P=0.0002). Overexpression of c-Met in DLBCL was significantly associated with better survival (P=0.0028) and remained significant in multivariate analysis with international prognostic index, thereby confirming c-Met as independent prognostic marker for better outcome in DLBCL. In vitro pharmacological c-Met inhibition and siRNA targeted against c-Met triggered caspase-dependent apoptosis. These findings provide evidence that c-Met is an independent prognostic marker for better outcome in Middle Eastern DLBCL. This data also enlightens the fact that c-Met through AKT kinase has a critical role in carcinogenesis of DLBCL, and strongly suggest that targeting c-Met may have therapeutic value in treatment of DLBCL.
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PMID:Inhibition of c-MET is a potential therapeutic strategy for treatment of diffuse large B-cell lymphoma. 2053 Dec 93

The inhibitor of apoptosis protein (IAP) family member X-linked inhibitor of apoptosis protein (XIAP) is essential for cell survival in lymphoma. However, the role of XIAP overexpression in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Therefore, we analysed the expression of XIAP protein and its clinicopathological correlation in a large cohort of DLBCLs by immunohistochemistry in a tissue micro-array format. XIAP was found to be overexpressed in 55% of DLBCLs and significantly associated with poor clinical outcome (p = 0.0421). To further elucidate the role of XIAP in DLBCL and the inter-relationship with PI3-kinase/AKT signalling, we conducted several in vitro studies using a panel of DLBCL cell lines. We found that pharmacological inhibition of XIAP led to caspase-dependent apoptosis in DLBCL cells. We also detected an inter-relationship between XIAP expression and activated AKT in DLBCL cells that may explain cellular resistance to PI3-kinase/AKT inhibition-mediated apoptosis. Finally, this anti-apoptotic effect was overcome by simultaneous pharmacological inhibition of XIAP and PI3-kinase/AKT signalling leading to a more potent synergistically induced apoptosis. In summary, our data suggest that XIAP expression is a poor prognostic factor in DLBCL and the XIAP-AKT relationship should be explored further as a potential therapeutic target in DLBCL.
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PMID:Prognostic significance of XIAP expression in DLBCL and effect of its inhibition on AKT signalling. 2063 85

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and P53 tumor suppressors are among the most commonly inactivated or mutated genes in human cancers, whose pathways cross-talk and interact in a complementary mode. In order to understand their roles and relationship in diffuse large B-cell lymphoma (DLBCL), we examined their expression and evaluated their prognostic significance in 62 patients with DLBCL treated with standard chemotherapy. Results showed that PTEN protein was lost in 23 (37.1%) cases, and the loss was associated with the activation of PI3K/AKT pathway, but was not associated with patient's clinical outcome. P53 mutation protein was detected in 30 (48.4%) cases and was associated with poor survival. Results of multivariate analysis showed that P53 mutation but not PTEN loss is associated with short survival in patients with DLBCL. PTEN status has no effect on P53 mutation-associated poor survival. We conclude that PTEN may play less prognostic role than P53 and that P53 mutation protein should be considered as a predictive factor of the need for a more aggressive therapy in patients with DLBCL who express P53.
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PMID:PTEN tumor suppressor plays less prognostic role than P53 tumor suppressor in diffuse large B-cell lymphoma. 2080 96

Growth factors and many oncogenes activate the lipid kinase phosphoinositide 3-kinase (PI3K), initiating a signaling cascade that includes the protein kinases AKT and target of rapamycin (TOR). The PI3K/AKT/TOR signaling pathway is a significant contributor to disease in various human cancers, including hematologic malignancies. Here we discuss different strategies to inhibit TOR for the treatment of leukemia, lymphoma, and myeloma. The TOR enzyme exists in two complexes in cells, TORC1 and TORC2. The majority of preclinical and clinical efforts to target TOR have involved using rapamycin and its analogs (rapalogs), which suppress TORC1 only partially and do not acutely inhibit TORC2. A new class of small molecules targeting the ATP-binding site of the TOR kinase, termed active-site TOR inhibitors (asTORi), achieves greater inhibition of both TOR complexes, resulting in broader suppression of the PI3K/AKT/TOR signaling network. Preclinical evidence suggests that asTORi have greater efficacy than rapalogs in Philadelphia chromosome-positive acute lymphoblastic leukemia and in T-cell lymphoma. These agents also show greater tolerability in animal models relative to rapalogs or inhibitors of PI3K. These findings encourage broader evaluation of asTORi efficacy in acute myeloid leukemia, B-cell lymphoma, myeloma, and other blood cancers.
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PMID:Target of rapamycin signaling in leukemia and lymphoma. 2082 59

Enzastaurin (LY317615.HCl) is currently in a phase III registration trial for diffuse large B-Cell lymphoma and numerous phase II clinical trials. Enzastaurin suppresses angiogenesis and induces apoptosis in multiple human tumor cell lines by inhibiting protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathway signaling. PI3K/AKT pathway signaling liberates eukaryotic translation initiation factor 4E (eIF4E) through the hierarchical phosphorylation of eIF4E binding proteins (4E-BP). When hypophosphorylated, 4E-BPs associate with eIF4E, preventing eIF4E from binding eIF4G, blocking the formation of the eIF4F translation initiation complex. Herein, we show that enzastaurin treatment impacts signaling throughout the AKT/mTOR pathway leading to hypophosphorylation of 4E-BP1 in cancer cells of diverse lineages (glioblastoma, colon carcinoma, and B-cell lymphoma). Accordingly, enzastaurin treatment increases the amount of eIF4E bound to 4E-BP1 and decreases association of eIF4E with eIF4G, thereby reducing eIF4F translation initiation complex levels. We therefore chose to evaluate whether this effect on 4E-BP1 was involved in enzastaurin-induced apoptosis. Remarkably, enzastaurin-induced apoptosis was blocked in cancer cells depleted of 4E-BP1 by siRNAs, or in 4EBP1/2 knockout murine embryonic fibroblasts cells. Furthermore, eIF4E expression was increased and 4E-BP1 expression was decreased in cancer cells selected for reduced sensitivity to enzastaurin-induced apoptosis. These data highlight the importance of modulating 4E-BP1 function, and eIF4F complex levels, in the direct antitumor effect of enzastaurin and suggest that 4E-BP1 function may serve as a promising determinant of enzastaurin activity.
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PMID:Modulation of 4E-BP1 function as a critical determinant of enzastaurin-induced apoptosis. 2097 26


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