Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Chemotherapy extends life and provides symptom palliation for patients with advanced non-small cell lung cancer (NSCLC). Numerous trials have been conducted that evaluate a variety of doublet regimens, but the majority of trials have found equal efficacy among the treatment arms. Indeed, a plateau appears to have been reached with respect to survival associated with traditional cytotoxic drug regimens. It was initially hoped that the addition of novel targeted agents to conventional chemotherapy would produce significant survival benefits for patients with advanced NSCLC; however, most trials have failed to show such a benefit. There is no survival benefit associated with adding erlotinib or gefitinib to a chemotherapy regimen, although there is a significant improvement in survival associated with erlotinib monotherapy in the second- and third-line advanced disease setting. In contrast, the results of E4599 clearly demonstrate that the addition of bevacizumab to paclitaxel-carboplatin chemotherapy extends survival in a select group of patients with non-squamous cell NSCLC. E4599 also represents a rational approach to drug development that could be modeled in other trials, namely, the use of a large, well designed, randomized trial prior to beginning a traditional phase II approach. This strategy can lead to the identification of subgroups most likely to benefit, as well as those that might experience increased toxicity, such as patients with squamous cell carcinoma treated with bevacizumab. Another approach to optimizing targeted therapy involves selecting a chemotherapy regimen with the greatest potential for synergy based on preclinical modeling. Because docetaxel has been shown to prolong survival in second-line treatment, a number of novel agents have been combined with docetaxel in order to improve efficacy. Alternatively, investigators have sought to combine novel agents with either carboplatin-paclitaxel or cisplatin-gemcitabine in first-line treatment. A number of trials are underway that combine these agents with inhibitors of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and the proteasome, as well as COX2 inhibitors, and novel immunomodulators.
Lung Cancer 2005 Dec
PMID:Optimizing chemotherapy and targeted agent combinations in NSCLC. 1655 71

Lung cancer continues to be a leading cause of death in the US, and in its most advanced stages remains incurable. Cytotoxic chemotherapies have been the standard of care for the treatment of unresectable disease. However, recent advances in the development of epidermal growth factor receptor (EGFR) inhibitors have led the way to a new generation of targeted biological agents. During the second annual symposium entitled 'the future of lung cancer: a translational focus', which was sponsored by the Physician s Education Resource, new strategies for the treatment of lung cancer were discussed. Besides the role of EGFR inhibitors, potential targets include the angiogenesis pathway; other growth factor pathways, such as phosphoinositol-3 kinase/Akt and Raf-MEK; the 26S proteasome, the histone deacetylase mechanism; and the TNF-related apoptosis-inducing factor receptors. Agents that are directed against these targets are all in varying stages of clinical development. As more is learned about their mechanisms of action and clinical spectrum of activity, the author anticipates their incorporation into novel regimens with enhanced activity against lung cancer.
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PMID:The second annual symposium on the future of lung cancer: a translational focus. 11-12 November 2005, Washington D.C., USA. 1670 87

The proteasome is an ubiquituous 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. Bortezomib (Velcade, formerly PS-341) 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. Clinical phase I trials, showed good tolerance of bortezomib 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 Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for this indication. A phase III trial comparing bortezomib to dexamethasone in refractory/relapsed multiple myeloma patients had to be halted due to a survival advantage in the bortezomib arm. Additional studies are focusing in 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 are ongoing with encouraging results, particularly in lung cancer and lymphoma.
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PMID:The proteasome: a novel target for anticancer therapy. 1676 5

Cisplatin is a potent cytotoxic agent commonly used for the treatment of solid tumors. However, tumor cell-acquired resistance to cisplatin-induced apoptosis is a major limitation for efficient therapy, as frequently observed in human lung cancer. Nitric oxide (NO) is a key regulator of apoptosis, but its role in cisplatin-induced cell death and the underlying mechanism are largely unknown. Previous studies indicate increased NO synthase activity and elevated NO production in lung carcinomas, which correlate with the incidence of chemotherapeutic resistance. Here, we show that NO impairs the apoptotic function of cells and increases their resistance to cisplatin-induced cell death in human lung carcinoma H-460 cells. The NO donors sodium nitroprusside and dipropylenetriamine NONOate were able to inhibit cisplatin-induced cell death, whereas the NO inhibitors aminoguanidine and 2-(4-carboxyphenyl)-4,4,5,5-tetra-methylimidazoline-1-oxyl-3-oxide had opposite effect. Cisplatin resistance in H-460 cells is mediated by Bcl-2, and NO up-regulates its expression by preventing the degradation of Bcl-2 via ubiquitin-proteasome pathway. Cisplatin-induced generation of reactive oxygen species causes dephosphorylation and degradation of Bcl-2. In contrast, generation of NO has no effect on Bcl-2 phosphorylation but induces S-nitrosylation of the protein, which inhibits its ubiquitination and subsequent proteasomal degradation. These findings indicate a novel pathway for NO regulation of Bcl-2, which provides a key mechanism for cisplatin resistance and its potential modulation for improved cancer chemotherapy.
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PMID:Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination. 1677 13

We showed that the PEA3 transcriptional factor interacted with LKB1, a serine/threonine kinase, which is somatically mutated in lung cancer. This interaction occurred through the ETS domain of PEA3 and the kinase domain of LKB1. Mutation of LKB1 in lung cancer cells stabilized PEA3. Reintroduction of wild-type (WT) LKB1 into cells induced down-regulation of PEA3 and subsequently resulted in reduced cyclooxygenase-2 RNA and protein expression, whereas germ-line and somatic LKB1 mutants were defective in this activity. LKB1 phosphorylated PEA3 and promoted its degradation through a proteasome-mediated mechanism. Cells expressing mutant LKB1 possessed greater invasive potential compared with cells expressing WT LKB1. Increased invasion of cells with mutant LKB1 was partly due to PEA3 expression, as RNA interference inhibition of PEA3 resulted in dramatic decrease of Matrigel invasion. However, forced expression of PEA3 resulted in down-regulation of epithelial markers and induction of mesenchymal markers. These results suggest that PEA3 stabilization due to LKB1 inactivation could lead to epithelial/mesenchymal transition and greater lung cancer invasion potential.
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PMID:LKB1/STK11 suppresses cyclooxygenase-2 induction and cellular invasion through PEA3 in lung cancer. 1691 60

Genetic knock out of the transcriptional co-repressor carboxyl-terminal-binding protein (CtBP) in mouse embryonic fibroblasts results in up-regulation of several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP levels. Previously, we have identified the homeodomain-interacting protein kinase 2 as such a regulator and demonstrated that HIPK2 activation causes Ser-422 phosphorylation and degradation of CtBP. In this study, we found that c-Jun NH2-terminal kinase 1 activation triggered CtBP phosphorylation on Ser-422 and subsequent degradation, inducing p53-independent apoptosis in human lung cancer cells. JNK1 has previously been linked to UV-directed apoptosis. Expression of MKK7-JNK1 or exposure to UV irradiation reduced cellular levels of CtBP via a proteasome-mediated pathway. This effect was prevented by JNK1 deficiency. In addition, sustained activation of the JNK1 pathway by cisplatin similarly triggered CtBP degradation. These findings provide a novel target for chemotherapy in cancers lacking p53.
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PMID:c-Jun NH2-terminal kinase promotes apoptosis by down-regulating the transcriptional co-repressor CtBP. 1698 92

Neuroendocrine differentiation is a common feature of lung cancer and increased numbers of neuroendocrine cells and their peptides have been described in chronic smokers. To understand the effects of cigarette smoking on the gene expression profile of neuroendocrine cells, microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals [normal nonsmokers, normal smokers, smokers with early chronic obstructive lung disease (COPD), and smokers with established COPD]. Of 11 genes considered to be neuroendocrine cell specific, only ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a member of the ubiquitin proteasome pathway, was consistently up-regulated in smokers compared with nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemical analysis of bronchial biopsies of smokers compared with nonsmokers. UCHL1 expression was evident only in neuroendocrine cells of the airway epithelium in nonsmokers; however, UCHL1 was also expressed in ciliated epithelial cells in smokers. This observation may add further weight to recent observations that ciliated cells are capable of transdifferentiating to other airway epithelial cells. In the context that UCHL1 is involved in the degradation of unwanted, misfolded, or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy.
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PMID:Up-regulation of expression of the ubiquitin carboxyl-terminal hydrolase L1 gene in human airway epithelium of cigarette smokers. 1710 9

The cyclooxygenase-2 (COX-2) inhibitor celecoxib is an approved drug in the clinic for colon cancer chemoprevention and has been tested for its chemopreventive and therapeutic efficacy in various clinical trials. Celecoxib induces apoptosis in a variety of human cancer cells including lung cancer cells. Our previous work has shown that celecoxib induces death receptor 5 expression, resulting in induction of apoptosis and enhancement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. In the current study, we further show that celecoxib down-regulated the expression of cellular FLICE-inhibitory protein (c-FLIP), a major negative regulator of the death receptor-mediated extrinsic apoptotic pathway, through a ubiquitin/proteasome-dependent mechanism independent of COX-2 in human lung cancer cells. Overexpression of c-FLIP, particularly FLIP(L), inhibited not only celecoxib-induced apoptosis but also apoptosis induced by the combination of celecoxib and TRAIL. These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-induced apoptosis and enhancement of TRAIL-induced apoptosis, which complements our previous finding that the extrinsic apoptotic pathway plays a critical role in celecoxib-induced apoptosis in human lung cancer cells. Collectively, we conclude that celecoxib induces apoptosis in human lung cancer cells through activation of the extrinsic apoptotic pathway, primarily by induction of death receptor 5 and down-regulation of c-FLIP.
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PMID:Cellular FLICE-inhibitory protein down-regulation contributes to celecoxib-induced apoptosis in human lung cancer cells. 1714 53

We previously established a highly metastatic subline, LNM35, from the NCI-H460 lung cancer cell line, and demonstrated upregulation of a novel gene, CLCP1 (CUB, LCCL-homology, coagulation factor V/VIII homology domains protein), in LNM35 and lung cancer specimens. In this study, we focused on the potential roles of that gene in cancer metastasis. First, we established stable LNM35 RNAi clones, in which CLCP1 expression was suppressed by RNAi, and found that their motility was significantly reduced, although growth rates were not changed. Next, in vitro selection of a phage display library demonstrated that a phage clone displaying a peptide similar to a sequence within the Sema domain of semaphorin 4B (SEMA4B) interacted with LNM35. Immunoprecipitation experiments confirmed interaction of CLCP1 with SEMA4B, regulation of CLCP1 protein by ubiquitination and proteasome degradation enhanced in the presence of SEMA4B. These results are the first to indicate that CLCP1 plays a role in cell motility, whereas they also showed that at least one of its ligands is SEMA4B and that their interaction mediates proteasome degradation by CLCP1. Although the physiological role of the interaction between CLCP1 and SEMA4B remains to be investigated, this novel gene may become a target of therapy to inhibit metastasis of lung cancers.
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PMID:CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. 1721 6

Curcumin, a well-known chemopreventive agent, has been shown to suppress the proliferation of a wide variety of tumor cells through a mechanism that is not fully understood. Cyclin E, a proto-oncogene that is overexpressed in many human cancers, mediates the G(1) to S transition, is a potential target of curcumin. We demonstrate in this report a dose- and time-dependent down-regulation of expression of cyclin E by curcumin that correlates with the decrease in the proliferation of human prostate and breast cancer cells. The suppression of cyclin E expression was not cell type dependent as down-regulation occurred in estrogen-positive and -negative breast cancer cells, androgen-dependent and -independent prostate cancer cells, leukemia and lymphoma cells, head and neck carcinoma cells, and lung cancer cells. Curcumin-induced down-regulation of cyclin E was reversed by proteasome inhibitors, lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal, suggesting the role of ubiquitin-dependent proteasomal pathway. We found that curcumin enhanced the expression of tumor cyclin-dependent kinase (CDK) inhibitors p21 and p27 as well as tumor suppressor protein p53 but suppressed the expression of retinoblastoma protein. Curcumin also induced the accumulation of the cells in G1 phase of the cell cycle. Overall, our results suggest that proteasome-mediated down-regulation of cyclin E and up-regulation of CDK inhibitors may contribute to the antiproliferative effects of curcumin against various tumors.
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PMID:Curcumin induces the degradation of cyclin E expression through ubiquitin-dependent pathway and up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor cell lines. 2698 69


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