Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteasome plays a critical role in the degradation of proteins involved in the regulation of cell cycle, apoptosis, and angiogenesis. Bortezomib is the first in a new class of antineoplastic agents known as proteasome inhibitors to become available for clinical use. Bortezomib targets pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27kip1, p53, nuclear factor-kB, Bcl-2, and Bax. In in vitro and in vivo, growth inhibition and apoptosis have been observed in tumor cells following exposure to bortezomib. Currently, bortezomib is approved for the treatment of patients with relapsed and/or refractory multiple myeloma who have received > or =2 therapies and progressed on their most recent therapy. Efforts are now being directed toward exploring the use of bortezomib in the treatment of advanced non-small-cell lung cancer (NSCLC). Clinical trials using bortezomib as monotherapy or in combinations, such as with taxanes, gemcitabine and platinums, and novel agents are under way, and preliminary results have demonstrated activity with bortezomib as a single agent and in combination with chemotherapy in advanced NSCLC. In addition, pharmacogenomics and biomarker analysis are being used in an attempt to identify tumor types likely to respond to treatment with bortezomib.
Clin Lung Cancer 2004 Dec
PMID:Use of proteasome inhibition in the treatment of lung cancer. 1563 66

Ornithine decarboxylase (ODC) is the rate-limiting enzyme involved in the biosynthesis of polyamines essential for cell growth and differentiation. Aberrant upregulation of ODC, however, is widely believed to be a contributing factor in tumorigenesis. Antizyme is a major regulator of ODC, inhibiting ODC activity through the formation of complexes and facilitating degradation of ODC by the 26S proteasome. Moreover, the antizyme inhibitor (AZI) serves as another factor in regulating ODC, by binding to antizyme and releasing ODC from ODC-antizyme complexes. In our previous report, we observed elevated AZI expression in tumor specimens. Therefore, to evaluate the role of AZI in regulating ODC activity in tumors, we successfully down-regulated AZI expression using RNA interference technology in A549 lung cancer cells expressing high levels of AZI. Two AZI siRNAs, which were capable to generate a hairpin dsRNA loop targeting AZI, could successively decrease the expression of AZI. Using biological assays, antizyme activity increased in AZI-siRNA-transfected cells, and ODC levels and activity were reduced as well. Moreover, silencing AZI expression decreased intracellular polyamine levels, reduced cell proliferation, and prolonged population doubling time. Our results directly demonstrate that downregulation of AZI regulates ODC activity, intracellular polyamine levels, and cell growth through regulating antizyme activity. This study also suggests that highly expressed AZI may be partly responsible for increased ODC activity and cellular transformation.
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PMID:Stable siRNA-mediated silencing of antizyme inhibitor: regulation of ornithine decarboxylase activity. 1567 Jul 71

Iron-regulatory protein 2 (IRP2), a posttranscriptional regulator of iron metabolism, undergoes proteasomal degradation in iron-replete cells, while it is stabilized in iron deficiency or hypoxia. IRP2 also responds to nitric oxide (NO), as shown in various cell types exposed to pharmacological NO donors and in gamma interferon/lipopolysaccharide-stimulated macrophages. However, the diverse experimental systems have yielded conflicting results on whether NO activates or inhibits IRP2. We show here that a treatment of mouse B6 fibroblasts or human H1299 lung cancer cells with the NO-releasing drug S-nitroso-N-acetyl-penicillamine (SNAP) activates IRP2 expression. Moreover, the exposure of H1299 cells to SNAP leads to stabilization of hemagglutinin (HA)-tagged IRP2, with kinetics analogous to those elicited by the iron chelator desferrioxamine. Similar results were obtained with IRP2(Delta)(73), a mutant lacking a conserved, IRP2-specific proline- and cysteine-rich domain. Importantly, SNAP fails to stabilize HA-tagged p53, suggesting that under the above experimental conditions, NO does not impair the capacity of the proteasome for protein degradation. Finally, by employing a coculture system of B6 and H1299 cells expressing NO synthase II or IRP2-HA cDNAs, respectively, we demonstrate that NO generated in B6 cells stabilizes IRP2-HA in target H1299 cells by passive diffusion. Thus, biologically synthesized NO promotes IRP2 stabilization without compromising the overall proteasomal activity. These results are consistent with the idea that NO may negatively affect the labile iron pool and thereby trigger responses to iron deficiency.
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PMID:Nitric oxide inhibits the degradation of IRP2. 1568 86

The retinoids are natural and synthetic derivatives of vitamin A. These cancer therapeutic and chemopreventive agents exert antiproliferative, differentiation-inducing, proapoptotic, and other biologic effects. The retinoids act through nuclear retinoid receptors to activate target genes that signal biologic effects. Agents that specifically activate the nuclear retinoid X receptors (RXRs) are known as rexinoids. Rexinoid growth suppression of human bronchial epithelial cells was linked to triggering of G1 cell cycle arrest, concomitant growth suppression, and a decrease in expression of G1 cyclins through activation of a proteasome-dependent degradation pathway. Clinical studies have demonstrated prolonged survival of subsets of patients with non-small-cell lung cancer (NSCLC) treated with rexinoids as single agents or as part of combination regimens. The critical role of RXR in downstream signaling makes rexinoids especially attractive agents to consider in combination therapy. There is encouraging evidence for therapeutic benefit of combination regimens of rexinoids with other targeted agents, such as epidermal growth factor receptor inhibitors, and with chemotherapy. Results from randomized phase III clinical trials in NSCLC will ultimately determine the impact for rexinoid-based therapy or chemoprevention for lung cancer.
Clin Lung Cancer 2005 Jan
PMID:Nonclassical retinoids and lung carcinogenesis. 1569 16

Proteasome inhibitors have emerged as promising anticancer therapeutic agents. Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies and has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. However, the molecular mechanisms of bortezomib-mediated apoptosis remain unclear. To characterize the mechanisms of apoptosis induction by proteasome inhibitors, we examined levels of Bcl-2 protein family members (Bik/NBK, Bax, Bak, Bcl-2, and Bcl-XL), release of cytochrome c, and activation of caspase-9 and -3 in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human lung cancer cell line H1299; and human ovarian cancer cell line SKOV3 after they were treated with bortezomib. The result showed that bortezomib induced rapid accumulation of Bik/NBK but not other Bcl-2 family members in all six cell lines. Bortezomib-mediated Bik/NBK accumulation and apoptosis were also observed in human embryonic kidney cells 293 and normal human bronchial epithelial cells. Moreover, dramatic Bik/NBK accumulation and apoptosis induction were observed when cells were treated with proteasome inhibitor MG132 and calpain inhibitor I (ALLN). Furthermore, no detectable changes in IkappaBalpha levels or in NFkappaB functionality were found after treatment with bortezomib. Finally, Bik/NBK accumulation was caused by stabilization of the protein from degradation and was associated with bortezomib cytotoxicity and apoptosis induction. Pretreatment of DLD1 cells with Bik/NBK siRNA reduced bortezomib-mediated Bik/NBK accumulation and cell death. Our results suggested that Bik/NBK is one of the mediators of proteasome inhibitor-induced apoptosis.
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PMID:Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. 1582 29

BAY 43-9006, a multikinase inhibitor that targets Raf, prevents tumor cell proliferation in vitro and inhibits diverse human tumor xenografts in vivo. The mechanism of action of BAY 43-9006 remains incompletely defined. In the present study, the effects of BAY 43-9006 on the antiapoptotic Bcl-2 family member Mcl-1 were examined. Treatment of A549 lung cancer cells with BAY 43-9006 diminished Mcl-1 levels in a time- and dose-dependent manner without affecting other Bcl-2 family members. Similar BAY 43-9006-induced Mcl-1 downregulation was observed in ACHN (renal cell), HT-29 (colon), MDA-MB-231 (breast), KMCH (cholangiocarcinoma), Jurkat (acute T-cell leukemia), K562 (chronic myelogenous leukemia) and MEC-2 (chronic lymphocytic leukemia) cells. Mcl-1 mRNA levels did not change in BAY 43-9006-treated cells. Instead, BAY 43-9006 enhanced proteasome-mediated Mcl-1 degradation. This Mcl-1 downregulation was followed by mitochondrial cytochrome c release and caspase activation as well as enhanced sensitivity to other proapoptotic agents. The caspase inhibitor Boc-D-fmk inhibited BAY 43-9006-induced caspase activation but not cytochrome c release. In contrast, Mcl-1 overexpression inhibited cytochrome c release and other features of BAY 43-9006-induced apoptosis. Conversely, Mcl-1 downregulation by short hairpin RNA enhanced BAY 43-9006-induced apoptosis. Collectively, these findings demonstrate that drug-induced Mcl-1 downregulation contributes to the proapoptotic effects of BAY 43-9006.
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PMID:The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. 1600 48

The proteasome is a ubiquitous enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis and angiogenesis. Since these pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the inhibition of proteasome is an attractive potential anticancer therapy. The present review will focus on the proteasome inhibitor bortezomib (Velcade, formerly PS-341; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA). Bortezomib is an extremely potent and selective proteasome inhibitor that shows strong activity in in vitro and in vivo laboratory studies against many solid and hematologic tumor types. Moreover, bortezomib, mainly by inhibition of the NF-kappaB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs. Based on these results, bortezomib entered clinical phase I trials, alone or in combination with chemotherapy, that showed good tolerance at doses that achieved a desired degree of proteasome inhibition. Phase II studies showed high response rates in refractory multiple myeloma patients, which led to the accelerated approval of bortezomib by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for this indication. A phase III trial comparing bortezomib with dexamethasone in refractory/ relapsed multiple myeloma patients had to be halted due to a survival advantage in the bortezomib arm. Additional studies are focusing on the potential benefit of bortezomib in newly diagnosed multiple myeloma patients. In other solid and hematological malignancies, phase II studies with bortezomib alone or in combination with other agents are ongoing. Encouraging results, particularly in lung cancer and lymphoma, have been observed. The critical molecules or genes responsible for tumor sensitivity to bortezomib continue to be evaluated using novel technologies.
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PMID:Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment. 1608 28

More effective therapies are needed for non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Proteasome inhibitors are one class of molecularly targeted antineoplastic agents being investigated for these diseases. These agents block the activity of the 26S proteasome, which is responsible for the degradation of the vast majority of intracellular proteins and thus affect multiple signaling pathways within cells. Bortezomib is the first proteasome inhibitor to be evaluated in human studies and is approved for use in multiple myeloma. Bortezomib is now being investigated as a potential treatment for NSCLC and SCLC. Preclinical studies have shown that single-agent bortezomib causes growth inhibition and apoptosis in numerous NSCLC cell lines in vitro and has antitumor activity in vivo. Bortezomib affects the levels of several proteins known to be of significance in lung cancers. Studies of bortezomib in combination with other antitumor agents in vitro and in vivo demonstrate that these combination regimens can offer additive/synergistic effects compared with the single agents. Bortezomib has been investigated in combination with taxanes, gemcitabine, carboplatin, histone deactylase inhibitors, and other molecularly targeted agents in various NSCLC cell lines. The sequence of administration of the agents in preclinical combination regimens in vitro and in vivo has been shown to be of significance; further elucidation of the mechanism of efficacy of bortezomib in lung cancer is required. Numerous clinical studies have been carried out or are ongoing. Bortezomib has the potential to play a significant role in the future management of NSCLC and SCLC.
Clin Lung Cancer 2005 Oct
PMID:Preclinical data with bortezomib in lung cancer. 1625 Sep 27

The 26S proteasome is a multicatalytic threonine protease complex that is responsible for intracellular protein turnover in eukaryotic cells. This complex degrades and processes proteins required for regulation of various cellular functions. Bortezomib is a novel proteasome inhibitor approved for therapy of multiple myeloma. Inhibition of ubiquitin-proteasome-mediated protein degradation by bortezomib leads to accumulation of its diverse substrates, including cyclins, transcriptional factors, tumor suppressor proteins, and protooncogenes. The sequelae of such profound perturbation of cellular function include cell cycle arrest and activation of apoptotic programs. As the development of this agent continues, there is interest in evaluating its interaction with other anticancer agents. This review provides an overview of selected interactions between bortezomib and other anticancer agents preclinically and in early clinical trials.
Clin Lung Cancer 2005 Oct
PMID:Sequencing bortezomib with chemotherapy and targeted agents. 1625 Sep 28

The combination of chemotherapy and radiation has been validated for the treatment of locally advanced non-small-cell lung cancer (NSCLC). However, the results are still unsatisfactory, and there is a need to improve current treatment. One approach is to use new agents that have the potential to enhance the efficacy of chemotherapy, radiation therapy (RT), or both. One potential target is the ubiquitin-proteasome pathway. This pathway plays an essential role in the degradation of most short- and long-lived intracellular proteins in eukaryotic cells and therefore regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib is a selective 26S proteasome inhibitor that has been approved for the treatment of multiple myeloma. Bortezomib has demonstrated in vitro chemotherapy- and RT-sensitizing properties as well as single-agent activity in lung cancer. This article will review the rationale for the use of bortezomib as part of the chemotherapy/RT strategy for the treatment of NSCLC.
Clin Lung Cancer 2005 Oct
PMID:The potential role of bortezomib in combination with chemotherapy and radiation in non-small-cell lung cancer. 1625 Sep 30


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