Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mounting evidence suggests that dynamic interactions between a tumor and its microenvironment play a critical role in tumor development, cell-cycle progression, and response to therapy. In this study, we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (NHL) cells to bone marrow stromal cells resulted in a reversible G(1) arrest associated with elevated p27(Kip1) and p21 (WAF1) proteins. The adhesion-mediated p27(Kip1) and p21 increases were posttranslationally regulated via the down-regulation of Skp2, a subunit of SCF(Skp2) ubiquitin ligase. Overexpression of Skp2 in MCL decreased p27(Kip1), whereas inhibition of Skp2 by siRNA increased p27(Kip1) and p21 levels. Furthermore, we found cell adhesion up-regulated Cdh1 (an activating subunit of anaphase-promoting complex [APC] ubiquitin ligase), and reduction of Cdh1 by siRNA induced Skp2 accumulation and hence p27(Kip1) degradation, thus implicating Cdh1 as an upstream effector of the Skp2/p27(Kip1) signaling pathway. Overall, this report, for the first time, demonstrates that cell-cell contact controls the tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHLs. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches for modifying tumor cell growth and response to therapy.
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PMID:Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. 1750 56

Constitutive activation of nuclear factor-kappaB (NF-kappaB) has been described in patient-derived Reed - Sternberg cells and Hodgkin lymphoma (HL) cell lines and contributes to the proliferation and survival of HL. Therapeutic inhibition of the proteasome with bortezomib may inhibit over-expression of nuclear NF-kappaB by preventing degradation of IkappaB, which sequesters NF-kappaB in the cytoplasm. To evaluate this hypothesis, the Cancer and Leukemia Group B (CALGB) conducted a multi-institutional phase II trial of single agent bortezomib in patients with relapsed or refractory classical HL. Thirty patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, 11 and every 21 days for a median of 2 cycles (range, 1 - 8). Patients were heavily pre-treated with a median of four prior therapies, and 83% were previously transplanted. No responses were observed, 9 patients had stable disease, and 21 progressed. The median progression-free and overall survivals were 1.4 months [95% CI, (1.28, 1.91)] and 14.8 months [95% CI (11.2, 22.3)], respectively. Grade 3 - 4 adverse events, primarily thrombocytopenia, occurred in 15 patients. Therefore, although well tolerated, 1.3 mg/m(2) bortezomib administered biweekly has no single agent activity in relapsed/refractory classical HL.
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PMID:Single agent bortezomib in the treatment of relapsed and refractory Hodgkin lymphoma: cancer and leukemia Group B protocol 50206. 1761 59

The Hodgkin cells and Reed-Sternberg cells (HRS) of classical Hodgkin lymphoma (CHL) are derived from germinal center B cells. The pathogenesis of CHL is unclear but constitutive activation of NFkappaB may contribute. Proteasome inhibition aimed at inhibiting NFkappaB has been shown to result in apoptosis in HRS cells. Here we investigated the effects of bortezomib, a proteasome inhibitor, in HRS cells with a combination of functional assays and gene expression profiling (GEP). Exposure of KMH2 and L428 cells to bortezomib resulted in inhibition of proliferation and induction of apoptosis. Gene expression analysis of KMH2 cells by oligonucleotide cDNA microarrays showed that a limited set of genes were differentially expressed involving several key cellular pathways including cell cycle and apoptosis. Among them, the caspase 8 inhibitor cFLIP was down-regulated and confirmed by Q-PCR. Given the evidence that cFLIP in HRS cells contribute to cells' insensitive to death receptor-mediated apoptosis, we combined bortezomib and TRAIL. This combination caused further down-regulation of cFLIP protein and increased apoptosis in CHL cells demonstrated by PARP p85 immunohistochemistry and immunoblotting. Such apoptotic effects were inhibited by caspase inhibitor z-VAD-FMK, confirming the pro-apoptotic effects of bortezomib and TRAIL are caspase-dependent. Bortezomib has no detectable effect on expression of TRAIL receptor DR4/DR5 in these two cell lines. Tissue microarray analysis of primary Hodgkin lymphomas displayed that 82% cases (95/116) expressed cFLIP in Reed-Sternberg cells. The discovery of apoptotic pathways that can be manipulated by proteasome inhibition provides rationale for the combination of bortezomib and agents such as TRAIL in CHL treatment.
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PMID:Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. 1765 39

Mantle cell lymphoma (MCL) still carries a poor prognosis. Chemoimmunotherapy (combination with rituximab) is the routine first-line therapy, although data strongly suggest a benefit from intensification through high-dose therapy with stem cell transplantation consolidation or dose-intense chemotherapy with HyperCVAD (fractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone)/rituximab. Unfortunately, most patients still experience relapse, and a multitude of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and first Food and Drug Administration-approved drug in MCL), mammalian target of rapamycin inhibitors, Bcl-2 inhibitors, and antiangiogenesis agents, among others. Because of the relative rarity of the disease-MCL represents 6% of non-Hodgkin lymphoma-an obvious effort is needed to enroll patients on clinical trials. Not surprisingly, as in other non-Hodgkin lymphomas, MCL appears more and more as a heterogeneous disease, which might impact future clinical trial design through pharmacogenomics and hopefully help us develop smaller "molecular" relevant trials.
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PMID:Expanding therapeutic options in mantle cell lymphoma. 1787 43

Bortezomib, a boronic acid, is a potent and selective proteasome inhibitor. The 20S proteasome is an enzyme complex present in cells, and it degrades many cell-cycle control factors, signal transduction factors, transcription factors, and oncogene and anti-oncogene products, thus controlling cell proliferation, differentiation, and apoptosis. Bortezomib is a novel molecular targeting agent which was designed to exhibit an antitumor effect by selectively inhibiting the 20S proteasome. Multiple myeloma is one of the incurable B-cell malignancies that continues to relapse with current treatment modalities, and the duration to progression becomes shorter in patients who repeatedly receive chemotherapy. There are no available treatment options in which durable efficacy can be expected after relapse; therefore, an effective therapy with a novel mechanism of action has been desired. In this review article, the results of clinical trials of bortezomib for multiple myeloma, including a Japanese phase I/II and pharmacokinetic/pharmacodynamic study, and those for non-Hodgkin lymphoma, especially for mantle cell lymphoma, are summarized. In the Japanese phase I/II study of bortezomib for relapsed multiple myeloma, this agent showed remarkable efficacy, with acceptable toxicities and unique pharmacokinetic/pharmacodynamic profiles, warranting further investigations, including more relevant administration schedules.
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PMID:Proteasome inhibitor, bortezomib, for myeloma and lymphoma. 1792 13

Mantle cell lymphoma (MCL) remains one of the more challenging sub-types of non-Hodgkin lymphoma. This entity, which is only approximately 10 years old, is characterized by response to many different chemotherapy regimens, though the duration of those responses remains often times quite short. Retreatment with second and third line combination regimens results in shorter and shorter durations of response, with the rapid emergence of a very drug-resistant phenotype. Despite these often frustrating clinical features, there is now a lot of new hope in managing patients with MCL. New insights into the molecular pathogenesis of MCL has revealed a plethora of new potential targets, while our continued efforts in novel targeted drug development has produced a host of agents that are already helping patients with this challenging disease. The use of proteasome inhibitors, for example, represents one example of a new strategy that has offered new hope for patients, and new opportunities for the physician treating this disease. In this review, we will put this biology into perspective, and describe how new revelations in MCL pathogenesis are leading to the identification of many exciting new drugs with promising activity.
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PMID:Mantle cell lymphoma: identifying novel molecular targets in growth and survival pathways. 1802 40

Bortezomib is the first of the proteasome inhibitors to be used clinically. Among the various cancers susceptible to proteasome inhibition are the non-Hodgkin's lymphomas. Mantle cell lymphoma appears to be particularly sensitive, leading to the FDA approval of bortezomib in patients who have received at least one prior therapy. This demonstration of clinical efficacy has led to an explosion of research attempting to further understand the anti-tumor effect of proteasome inhibition and clinical investigations exploring bortezomib in combination with other agents. In this review, we will detail the clinical results and ongoing trials utilizing bortezomib in Hodgkin's and non-Hodgkin's lymphoma.
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PMID:The role of bortezomib in the treatment of lymphoma. 1805 74

Mantle cell lymphoma (MCL) represents 6% of non-Hodgkin lymphomas, but is one of the most active fields of clinical investigation. Unfortunately, there is still no standard or curative therapy in MCL. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyperfractionated cyclophosphamide, vincristine, adriamycin/doxorubicin and dexamethasone/rituximab. Most patients still relapse and a multitude of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and the first US FDA-approved drug for MCL), mTOR inhibitors, Bcl-2 inhibitors, antiangiogenesis agents and histone deacetylase inhibitors among others. An obvious effort is needed to enroll patients on clinical trials, the design of which might benefit from pharmacogenomics and a better understanding of MCL biology and its diversity.
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PMID:Bortezomib in mantle cell lymphoma. 1840 30

Proteasome inhibitors and immunomodulatory drugs (IMiDs) have demonstrated clinical potential as novel therapies for non-Hodgkin lymphoma (NHL). Bortezomib, a peptide aldehyde derivative that inhibits the proteasome by binding directly to its active sites, is the most extensively studied agent in the clinical setting. Single-agent bortezomib is effective in several lymphoid malignancies, and is recommended for second-line treatment of mantle-cell lymphoma (MCL). Ongoing trials are investigating the combination of bortezomib with chemotherapy, and with agents that target Bcl-2 proteins. Although proteasome inhibitors are potentially potent anti-tumor drugs, the pleotropic nature of their biological effects means that further research is required to elucidate the optimal combinations, doses and schedules. In addition to proteasome inhibitors, the IMiDs, such as lenalidomide, have the potential to improve outcomes for patients with NHL. These drugs inhibit cell growth and proliferation by several mechanisms, including blocking the effect of growth factors and stimulating T cells and natural killer cells. Lenalidomide is particularly effective in lymphoproliferative disorders such as multiple myeloma, and is active in patients with various forms of NHL, with a favourable side-effect profile. Complimentary clinical and pharmacological features suggest that lenalidomide may be effective when combined with monoclonal antibodies. Ongoing and future studies will provide further information.
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PMID:Novel approaches for the treatment of NHL: Proteasome inhibition and immune modulation. 1882 34

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in preventing colorectal cancer. Apoptosis induction by NSAIDs plays a critical role in NSAID-mediated chemoprevention. Our previous study demonstrated that NSAIDs require the proapoptotic B-cell non-Hodgkin lymphoma-2 (Bcl-2) family member Bcl-2-associated x protein (BAX) to induce apoptosis and inhibit the expression of antiapoptotic basal cell lymphoma-extra large (Bcl-X(L)) in colon cancer cells. In this study, we further investigated how BAX and Bcl-X(L) mediate NSAID-induced apoptosis. We found that Bcl-X(L) is downregulated by NSAIDs in part through proteasome-mediated protein degradation. NSAIDs promote the dissociation of BAX and Bcl-X(L) and translocation of BAX to the mitochondria. Furthermore, we found that only wild-type BAX, but not a mutant BAX deficient in either protein-protein interaction or mitochondrial localization, was able to restore NSAID-induced apoptosis in the BAX-knockout colon cancer cells. These results suggest that NSAIDs induce apoptosis in colon cancer cells by dissociating BAX and Bcl-X(L), thereby promoting BAX mitochondrial translocation and multimerization.
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PMID:NSAIDs downregulate Bcl-X(L) and dissociate BAX and Bcl-X(L) to induce apoptosis in colon cancer cells. 1900 86


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