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)

Recent studies have demonstrated that antineoplastic activity of Cox-2 inhibitors may depend on targets other than Cox: among those, nuclear factor kappaB (NFkappaB) seems the most promising. Although preclinical studies have suggested that aspirin and Cox-2 inhibitors may influence the progression of lung cancer, the molecular mechanisms of these protective effects in this tumor type has not been fully elucidated. We investigated the effects of celecoxib and aspirin in the induction of apoptosis and in the ability to activate NFkappaB in three non-small cell lung cancer cell lines. Apoptosis was evaluated by FACS, caspase activation assay and expression of apoptosis-related genes by RT-PCR, while NFkappaB activation was assessed by immunofluorescence. No apoptotic response was observed after treatment with both high and low dose of celecoxib. Nevertheless, celecoxib at both concentrations induced a strong NFkappaB activation, with increased expression of NFkappaB-dependent genes, such as bcl-2, bcl-XL and survivin. Similarly, aspirin at both concentrations did not induce any apoptotic response, but activated NFkappaB in a dose-dependent manner. This study supports the hypothesis that NFkappaB activation is an important effect of NSAIDs in lung cancer, leading to apoptosis resistance. This effect of both aspirin and celecoxib may be considered undesirable in lung cancer chemoprevention.
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PMID:Failure of apoptosis and activation on NFkappaB by celecoxib and aspirin in lung cancer cell lines. 1734 22

Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua, is an effective novel antimalarial drug. Recent studies suggest that it also has anticancer effects. The present study investigated the apoptosis activity of DHA in cultured human lung cancer cells by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay and flow cytometry. Intracellular free calcium concentrations in the lung cancer cells were evaluated by laser scanning confocal microscopy using Fura-3/AM as probe. The observations also indicated that DHA downregulated the mRNA and protein expression level of survivin in the lung cancer cell line SPC-A-1 cells, whereas it did not affect those of caspase-4. These results demonstrated that DHA can induce apoptosis of lung cancer cell line SPC-A-1 cells and that calcium and survivin participated in the apoptotic signalling pathways.
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PMID:Calcium and survivin are involved in the induction of apoptosis by dihydroartemisinin in human lung cancer SPC-A-1 cells. 1734 42

Taurolidine and povidone-iodine (PVP-I) are used in every day clinical practice, taurolidine as a broad spectrum antibiotic, and PVP-I as an antiseptic. The type of cell death induced in malignant pleural mesothelioma (MPM) cell lines by these agents was compared, and their ability to sensitize to chemotherapy assessed. Both taurolidine and PVP-I inhibited MPM cell growth after 7.5min incubation, but taurolidine was more effective at later time points and was more specific towards tumour cells than PVP-I. Taurolidine induced death by caspase-dependent and independent mechanisms, whereas in contrast, PVP-I induced a necrotic phenotype that was not caspase-dependent. Interestingly, both taurolidine and PVP-I induced the production of reactive oxygen intermediates and decreased mitochondrial membrane permeability, and cell death was inhibited by the oxygen scavenger N-acetyl cysteine. Taurolidine but not PVP-I treatment resulted in p53 activation in 2/3 MPM cell lines and a decrease in the protein levels of survivin, Bcl-2 and Mcl-1. Survivin also decreased in response to PVP-I whereas Bcl-xL remained unaffected by both treatments. Targeting of Bcl-xL with siRNA sensitized MPM cells to taurolidine and taurolidine treatment sensitized MPM cells to cisplatin-induced apoptosis. In conclusion, taurolidine and PVP-I are both cytotoxic to human MPM cells at early and late time points and induce reactive oxygen intermediate production. Taurolidine induces apoptosis and necrosis, activates p53 and sensitizes cells to cisplatin, whereas PVP-I inhibits cell growth via necrosis. Both agents are promising candidates for use in local treatment within multimodality concepts for MPM.
Lung Cancer 2007 Jun
PMID:Taurolidine and povidone-iodine induce different types of cell death in malignant pleural mesothelioma. 1738 50

The proteasome inhibitor PS-341 (Bortezomib, Velcade) is currently being combined with taxanes in several clinical trials for treatment of patients with various solid tumors including lung cancers. It has been shown that the combination of Docetaxel (DTX) and PS-341 generates either enhanced or antagonized antitumor effects in different types of cancer in preclinical settings. However, the preclinical evaluation of the DTX and PS-341 combination in human lung cancer cells has not been reported. In this study, the effects of DTX combined with PS-341 on cell survival and apoptosis induction in a panel of human non-small cell lung cancer (NSCLC) cell lines were assessed. We found that PS-341 when combined with DTX led to either enhanced or antagonistic effects on the decrease of cell survival and the induction of apoptosis depending on cell lines and treatment schedules. In general, a treatment schedule administering DTX first followed by PS-341 works better than other schedules in decreasing cell survival and inducing apoptosis. In addition, we examined several molecules regulated by DTX, PS-341, or both agents in order to reveal the underlying mechanisms of synergy and antagonism. Our results suggest that Bcl-2 and survivin are two important proteins that may determine cells' response to DTX/PS-341-induced apoptosis.
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PMID:Assessment of apoptosis-inducing effects of docetaxel combined with the proteasome inhibitor PS-341 in human lung cancer cells. 1738 69

Double-stranded decoy oligodeoxynucleotide (ODN) is a promising approach for inhibiting gene transcription. Signal transducer and activator of transcription (STAT) 3, a potent transcription factor, is usually constitutively activated in a variety of malignancies, and considered as an attractive drug target. In this study, it was noted that STAT3 was overactivated in human lung cancer cells, and STAT3-decoy ODN, which was high-efficiently transfected into nucleus of cancer cells, significantly inhibited the proliferation of PG cells by inducing apoptosis or cell cycle arrest. The transcription levels of mcl-1, cyclin D1, bcl-xl and survivin were significantly decreased by 64.4, 56.1, 72.8% (P<0.01) and 31.8% (P<0.05), respectively; and the synthesis levels of bcl-xl and cyclin D1 in PG cells showed 64.5% (P<0.01) and 28.6% (P<0.05) decrease, respectively. Our study demonstrated that decoy-ODN targeting at activated STAT3 may potentially be used as an anti-lung cancer therapeutic approach.
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PMID:STAT3-decoy oligodeoxynucleotide inhibits the growth of human lung cancer via down-regulating its target genes. 1748 94

Only a handful of NSCLC patients have been included in dendritic cell (DC) vaccine clinical trials. We had previously reported a series of 16 individuals with stages IA-IIIB NSCLC who received autologous DC vaccines matured with dendritic cell/T cell-derived maturation factor (DCTCMF). Here we report the results of a continuation study with similar inclusion criteria, immunization protocol, and analysis, using an immature DC vaccine. Of the 14 participants, 7 had undergone surgical resection (stage I/II), with or without adjuvant therapy, and 7 with unresectable stage III had been treated with chemo-radiation alone. Autologous DCs were pulsed with apoptotic bodies derived from an allogeneic NSCLC cell line that over-expresses Her2/neu, CEA, WT1, Mage2, and survivin. DCs were not exposed to any maturation stimulus. Individuals received two intradermal vaccines (average 8.1x10(7) DC per immunization) 1 month apart. Immune responses were measured by IFN-gamma ELISPOT, comparing relative number of antigen-reactive T-cells from pre-vaccine to timepoints post-immunization. Immunologic responses were seen in 4/7 stage III unresectable, and 6/7 stage I/II surgically resected patients, including 3/3 resected patients who had also received adjuvant chemo-radiation. There were no related adverse events. One of seven surgically resected patients recurred and 4/7 stage III patients progressed. Three of five patients with progressive disease showed no immunologic response. Data indicate that immature DC pulsed with apoptotic tumour cells have similar biologic activity to a DCTCMF-matured DC preparation delivered in a similar clinical protocol. Therapeutic efficacy is unknown and clinical outcomes are anecdotal.
Lung Cancer 2007 Sep
PMID:Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. 1750 25

The proteasome inhibitor PS-341 (bortezomib or Velcade), an approved drug for treatment of patients with multiple myeloma, is currently being tested in clinical trials against various malignancies, including lung cancer. Preclinical studies have shown that PS-341 induces apoptosis and enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human cancer cells with undefined mechanisms. In the present study, we show that PS-341 induced caspase-8-dependent apoptosis, cooperated with TRAIL to induce apoptosis, and up-regulated death receptor 5 (DR5) expression in human non-small cell lung cancer (NSCLC) cells. DR5 induction correlated with the ability of PS-341 to induce apoptosis. Blockage of PS-341-induced DR5 up-regulation using DR5 small interfering RNA (siRNA) rendered cells less sensitive to apoptosis induced by either PS-341 or its combination with TRAIL, indicating that DR5 up-regulation mediates PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis in human NSCLC cells. We exclude the involvement of c-FLIP and survivin in mediating these events because c-FLIP (i.e., FLIP(S)) and survivin protein levels were actually elevated on exposure to PS-341. Reduction of c-FLIP with c-FLIP siRNA sensitized cells to PS-341-induced apoptosis, suggesting that c-FLIP elevation protects cells from PS-341-induced apoptosis. Thus, the present study highlights the important role of DR5 up-regulation in PS-341-induced apoptosis and enhancement of TRAIL-induced apoptosis in human NSCLC cells.
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PMID:The proteasome inhibitor PS-341 (bortezomib) up-regulates DR5 expression leading to induction of apoptosis and enhancement of TRAIL-induced apoptosis despite up-regulation of c-FLIP and survivin expression in human NSCLC cells. 1751 Apr 29

Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm that is resistant to chemotherapy. Bortezomib is an FDA-approved proteasome inhibitor that is currently under clinical investigation in multiple neoplasms but has not been studied extensively in MPM. In this report, we determine the biological and molecular response of cultured MPM cells to bortezomib alone and in combination with cisplatin or pemetrexed. We used four MPM cell lines (MS589, H28, H2052, JMN), a normal mesothelial cell line (HM3), and a lung cancer cell line (H23) in survival studies utilizing bortezomib, cisplatin, and pemetrexed alone and in combination by administering concurrently or by varying the order of administration. We determined the effect of bortezomib on the cell cycle, apoptosis, and on the expression of cell cycle proteins p21/WAF1 and p27/KIP1 and on apoptosis-related proteins IAP-1, IAP-2, survivin, and XIAP. Bortezomib was highly cytotoxic to MPM cells and induced both G(2)/M and G(1)/S cell cycle arrest. Apoptosis increased in a concentration- and time-dependent manner in 3 of 4 MPM cell lines. Bortezomib stabilized or increased protein levels of p21/WAF1 and IAP-1 and to a lesser degree p27/KIP1, IAP-2, XIAP, and survivin. In combination studies with cisplatin, bortezomib was generally synergistic at high concentrations and antagonistic at low concentrations. Bortezomib increased the cytotoxicity of cisplatin and pemetrexed in a concentration-dependent manner when administered prior to either. Bortezomib may improve outcome in MPM patients alone or in combination with standard chemotherapy but the order of administration is likely to be important. This study justifies further evaluation of bortezomib in MPM.
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PMID:Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma. 1752 64

The natural flavonoid quercetin has been suggested by epidemiological studies to have preventive activity against lung cancer; however, the mechanism of which has not been well elucidated. In this report, we demonstrate that quercetin significantly enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells. Quercetin increased expression of death receptor (DR) 5, whereas it had no effect on that of other components of the death-inducing signaling complex. Conversely, the expression of survivin was potently inhibited by quercetin. We further determined that Protein Kinase C (PKC) is essential for DR5 induction but is dispensable for suppression of survivin expression. In contrast, the blockage of the serine/threonine kinase Akt activity by quercetin is important for inhibition of survivin expression but not induction of DR5. These results suggest the pathways for regulation of DR5 and survivin expression by quercetin are distinct. Importantly, suppression of survivin-sensitized TRAIL-induced cell death and blockage of DR5 expression suppressed the synergistic cytotoxicity induced by quercetin and TRAIL co-treatment. On the whole, our data show that quercetin sensitizes TRAIL-induced cytotoxicity in lung cancer cells through two independent pathways: induction of DR5 and suppression of survivin expression, which may underlie the mechanism of the lung cancer preventive activity of quercetin. The potentiation of TRAIL-induced NSCLC cell death could be implicated in lung cancer therapy and prevention.
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PMID:Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL-induced cytotoxicity by quercetin in non-small cell lung cancer cells. 1754

Lung cancer is the leading cause of cancer mortality in the United States. Despite advances made over the past decades, the overall survival of patients with lung cancer remains dismal. Here we report novel G-quartet oligodeoxynucleotides (GQ-ODN) that were designed to selectively target signal transducer and activator of transcription 3 (Stat3), in the treatment of human non-small cell lung cancer (NSCLC). The objective of this study was to evaluate the effects of two novel GQ-ODN STAT3 inhibitors, T40214 and T40231, on NSCLC bearing nude mice. NSCLC bearing nude mice were assigned to 5 groups, which were treated by vehicle, control ODN, T40214, T40231, and Paclitaxel, respectively. Tumors were measured, isolated and analyzed using Western blotting, immuno-histochemistry, RPA and TUNEL. Results show that GQ-ODN T40214 and T40231 significantly suppress the growth of NSCLC tumors in nude mice by selectively inhibiting the activation of Stat3 and its downstream proteins Bcl-2, Bcl-xL, Mcl-1, survivin, VEGF, Cyclin D1 and c-myc; thereby, promoting apoptosis and reducing angiogenesis and cell proliferation. These findings validate Stat3 as an important molecular target for NSCLC therapy and demonstrate the efficacy of GQ-ODN in inhibiting Stat3 phosphorylation.
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PMID:Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides. 1754 13


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