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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aflatoxin B1 (AFB1) is a potent dietary hepatocarcinogen in animals and probably in humans. Mutations (and altered expression) of the tumor suppresser gene p53 have been observed in liver tumors from patients exposed to high dietary AFB1. Inhalation of AFB1-laden grain dusts has been associated with an increased incidence of lung cancer in humans as well. We examined the effects of low concentrations of AFB1 on the expression of p53 and MDM2 in human bronchial epithelial cells (BEAS-2B) transfected with cDNA for either cytochrome P450 (CYP) 1A2 (B-CMV1A2) or CYP 3A4 (B3A4), two isozymes that are responsible for AFB1 activation in human liver and possibly the lung. Untreated B-CMV1A2 and B3A4 cells constitutively expressed p53. Exposure to a range (0.015-15 microM for 30 min) of AFB1 concentrations caused a concentration-dependent decline in p53 expression in B-CMV1A2 cells, and to a lesser extent, in B3A4 cells. The AFB1-mediated decrease in p53 continued for at least 12 h after 30-min exposures to 1.5 muM AFB(1). Mirroring the decrease in p53 expression was a concentration-dependent increase in the expression of the 76-kDa MDM2 isoform in B-CMV1A2 and B-3A4 cells. Interestingly, AFB1 did not induce DNA laddering, an indicator of apoptotic cell death, but proteolytic activation of caspase-3 was detected in AFB1-treated B-CVM1A2 cells. In total, these data show that low, environmentally-relevant concentrations of AFB1 alter the expression of p53 and MDM2 in these human lung cells, and that cells that stably express CYP 1A2 were more susceptible to this effect than nontransfected, or 3A4-expressing cells.
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PMID:Aflatoxin B1 alters the expression of p53 in cytochrome P450-expressing human lung cells. 1628 Mar 84

Lung cancer is the leading cause of cancer death in many developed countries, including Taiwan. Quercetin, a widely distributed bioflavonoid, is well known to induce growth inhibition in a variety of human cancer cells. Quercetin glucuronides are the main circulating metabolites after dietary supplements with quercetin in humans. However, there is little information available as to how quercetin glucuronides affect human cancer cells. We investigated the effects of quercetin glucuronides in a human lung cancer cell line NCI-H209. We checked the cell viability, cell cycle checkpoint proteins, pro- and antiapoptotic proteins, caspase-3 activity, and gene expression by flow cytometry and Western blot. The viability of cells decreased in a dose- and time-dependent manner. Cell cycle analysis revealed a significant increase of the proportion of cells in G2/M phase and subG0/G1 phase (corresponding to apoptotic cells). Moreover, quercetin glucuronides increased the expressions of cyclin B, Cdc25c-ser-216-p, and Wee1 proteins, indicating the G2/M arrest. We also demonstrated a concurrent decrease of the mitochondrial membrane potential, release of cytochrome c, up-regulation of Bax, down-regulation of Bcl-2, and activation of caspase-3, and subsequently, cleavage of poly(ADP-ribose) polymerase. In addition, quercetin glucuronide-induced apoptosis was totally blocked by the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone. Taken together, we demonstrated that quercetin glucuronides inhibited proliferation through G2/M arrest of the cell cycle and induced apoptosis via caspase-3 cascade in the human lung cancer cell line NCI-H209. Delineation of the biological effects of specific major quercetin metabolites on chemotherapeutic potential or chemoprevention of human cancers warrants further investigation.
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PMID:Inhibition of lung cancer cell growth by quercetin glucuronides via G2/M arrest and induction of apoptosis. 1628 Apr 56

Lung cancer is the leading cause of cancer-related deaths throughout the world. Extracts of medicinal plants are believed to contain different chemopreventive or chemotherapeutic compounds. In this study, we determined the anti-cancer property of one of the traditional Indian medicine Rasagenthi Lehyam (RL) for the treatment of lung cancer. Two lung cancer cell lines (A-549 and H-460) and one normal bronchial epithelial (BEAS-2B) cell line were used to test the chemotherapeutic effect of RL. Out of five fractions of RL, chloroform fraction of RL (cRL) demonstrated a significant inhibition of cell proliferation and induction of apoptosis in A-549 and H-460 cells but not in normal BEAS-2B cells. The cRL fraction up-regulated the pro-apoptotic genes p53 and Bax and induced caspase-3 activation, and down-regulated the pro-survival gene Bcl-2 in both the lung cancer cell lines. Also, nuclear export of p53 was seen in cRL-treated lung cancer cells. In addition, cRL induced G2/M arrest of cell cycle and enhanced the radio-sensitivity of both the lung cancer cell lines. This study suggests that cRL may prove to be a potent anti-cancer agent that may be used for the treatment of lung cancer. However, further studies are required to bring cRL into the mainstream of medicine in the treatment of lung cancer.
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PMID:A herbal medicine for the treatment of lung cancer. 1631 13

Previously, we found that 3,4-(methylenedioxy)-1-(2',3'-epoxypropyl)-benzene (safrole oxide) induced a typical apoptosis in A549 human lung cancer cells by activating caspase-3, -8, and -9. In this study, we further investigated which upstream pathways were activated by safrole oxide during the apoptosis. Immunofluorescence assay combined with laser scanning confocal microscopy revealed that both Fas and Fas ligand (FasL) were up-regulated by the small molecule. In addition, Fas protein distribution was altered, showing a clustering distribution instead of a homogeneous one. Subsequently, Western blot analysis confirmed the up-regulations of Fas and its membrane-binding form of FasL (m-FasL), as well as P53 protein. Conversely, safrole oxide hardly affected integrin beta4 subunit expression or distribution, which was reflected from the data obtained by immunofluorescence assay combined with laser scanning confocal microscopy. The results suggested that Fas/FasL pathway might be involved in safrole oxide-induced apoptosis of A549 cells, while integrin beta4 might be irrelevant to the apoptosis. Nevertheless, we first found the strong expression of integrin beta4 in A549 cells. The study first suggested that safrole oxide might be used as a small molecular promoter of Fas/FasL pathway to elicit apoptosis in A549 cells, which would lay the foundation for us to insight into the new strategies for lung cancer therapy.
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PMID:Safrole oxide induces apoptosis by up-regulating Fas and FasL instead of integrin beta4 in A549 human lung cancer cells. 1632 5

The emergence of resistance to chemotherapy remains a principle problem in the treatment of small-cell lung cancer (SCLC). We demonstrate that extracellular matrix (ECM) activates phosphatidyl inositol 3-kinase (PI3-kinase) signaling in SCLC cells and prevents etoposide-induced caspase-3 activation and subsequent apoptosis in a beta1 integrin/PI3-kinase-dependent manner. Crucially we show that etoposide and radiation induce G2/M cell cycle arrest in SCLC cells prior to apoptosis and that ECM prevents this by overriding the upregulation of p21(Cip1/WAF1) and p27(Kip1) and the downregulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3-kinase signaling. Importantly we show that chemoprotection is not mediated by altered SCLC cell proliferation or DNA repair. Thus, ECM via beta1 integrin-mediated PI3-kinase activation overrides treatment-induced cell cycle arrest and apoptosis, allowing SCLC cells to survive with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance.
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PMID:ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through beta1 integrin-dependent activation of PI3-kinase. 1641 Jul 97

Depletion of intracellular potassium ions (K+) is necessary for cells to shrink, activate caspases and induce DNA fragmentation, events which are features of apoptosis. Here we describe a 96-well plate method using the cell permeable form of K+ binding benzofuran isophtalate (PBFI-AM) to measure intracellular K+ content in relation to untreated control. Cultured human pulmonary mesothelioma cells (P31) and small-cell lung cancer cells (U1690) were treated with K+ flux modulators in order to deprive the cells of intracellular K+. The combination of K+ influx inhibition with 10 micromol/L bumetanide plus 10 micromol/L ouabain and K+ efflux stimulation with 3 mg/L amphotericin B or 5 micromol/L nigericin efficiently reduced the intracellular K+ content after 3 h. Manipulation of K+ fluxes with subsequent intracellular K+ depletion induced apoptosis of lung cancer cells, as detected by caspase-3 activity after 3 h K+ depletion followed by 24 h proliferation and TUNEL positive staining after 48 h proliferation. We concluded that the PBFI-AM assay was a useful tool to determine intracellular K+ content in relation to untreated control, and that intracellular K+ depletion of lung cancer cells by clinically used drugs of relevant concentrations induced apoptosis. These findings may lead to novel therapeutic strategies in the treatment of lung cancer.
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PMID:Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells. 1648 38

Lung cancer is one of the most common causes of cancer death worldwide. Although recent advances in chemotherapy and radiation therapy have yielded modest improvements in patient outcomes, overall survival remains poor. Therefore, new therapeutic targets are needed. Phosphoinositide-dependent kinase-1 (PDK1) is one potential target. The aim of the present studies was to investigate the potential of a celecoxib-derived PDK1 inhibitor (OSU03013), that does not inhibit cyclooxygenase-2, to kill lung cancer cells in vitro. Using human non-small-cell lung cancer A549 cells, OSU03013 dose-dependently induced apoptosis. After 6 h of treatment with 7.5 microM OSU03013, 26% of the cells were apoptotic, compared to 4% of the control cells as determined by measuring the sub-G1 peak of propidium iodide stained cells with flow cytometry. A similar increase in apoptosis was evident using the Cell Death ELISA assay. OSU03013-induced apoptosis was accompanied by a reduction in the mitochondrial membrane potential, the release of cytochrome c and the cleavage of caspase-3. Surprisingly, the phosphorylation of Akt at serine 473 was increased in A549 cells treated with 7.5 microM OSU03013. However, the toxicity of OSU03013 was reduced in A549 cells expressing a constitutively active form of Akt. These data demonstrate that OSU03013 induces apoptosis in A549 cells via the mitochondrial pathway. Inhibition of the Akt pathway appears uninvolved in this toxicity, although Akt can provide protection. These results also suggest the potential of celecoxib-derived agents to treat some forms of lung cancer.
Lung Cancer 2006 Apr
PMID:Cytotoxicity of a non-cyclooxygenase-2 inhibitory derivative of celecoxib in non-small-cell lung cancer A549 cells. 1649 9

Direct delivery of chemotherapeutic agents to the lung can increase both the drug concentration and exposure period to lung tumours. The objective of this study was to formulate docetaxel (DOC) into a metered dose inhaler (MDI), assess its aerodynamic characteristics and to evaluate the effect of celecoxib (CXB), a cyclooxygenase-2 (COX-2) inhibitor, on the in-vitro cytotoxicity and apoptotic response of aerosolized DOC against human lung adenocarcinoma cell line A549. A stable solution-type MDI formulation was developed with 0.25% DOC and 15% w/w ethyl alcohol using HFA 134a propellant. The formulation was evaluated for medication delivery, mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), percent throat deposition, respirable mass and respirable fraction. A six-stage viable impactor was used to assess the in-vitro cytotoxicity of DOC-MDI alone or in combination with CXB. Induction of apoptosis in A549 cells by DOC (non-aerosolized and aerosolized) in combination with CXB was evaluated by established techniques, such as caspase-3 estimation and terminal deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) staining. The influence of different treatments on the expression of COX-2 and peroxisome proliferator-activated receptor-gamma(PPAR-gamma) in A549 cells was studied by RT-PCR. The DOC-MDI formulation had a MMAD of 1.58 microm, (GSD = 3.2) and a medication delivery of 80 microg/shot. DOC-MDI (one shot) in combination with CXB (10 microg mL(-1)) had a cell kill of more than 80% as determined by in-vitro cytotoxicity assay. The specific caspase-3 activity in A549 cells treated with DOC (0.01 microg mL(-1)) and CXB (10.0 microg mL(-1)) combination was 4 times higher than CXB and untreated control group, respectively. Further, TUNEL staining showed significant apoptosis of A549 cells treated with aerosolized DOC alone or in combination with CXB when compared with CXB and untreated cells. The RT-PCR experiments showed similar expression of COX-2 in both control and treated groups. PPAR-gamma expression was increased in the combination treatment (0.01 microg mL(-1) DOC and 10 microg mL(-1) CXB) as compared with control (untreated), DOC (0.01 microg mL(-1)) and CXB (10 microg mL(-1)) treatments. Our results indicate the potential of inhalation delivery of DOC in the treatment of lung cancer.
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PMID:Anti-cancer effect of celecoxib and aerosolized docetaxel against human non-small cell lung cancer cell line, A549. 1653 99

Ponicidin, an ent-kaurane diterpenoid derived from a constituent of the herbal supplement PC-SPES, Rabdosia rubescens, is recently reported to have anti-tumor effects on a large variety of cancers. In this study, we demonstrate that ponicidin exhibits cytotoxicity, induces apoptosis, disrupts the mitochondrial membrane potential, and triggers the activation of caspase-3, -8 and -9 in lung cancer A549 and GLC-82 cells. Ponicidin treatment of lung cancer cells caused downregulation of anti-apoptotic protein Bcl-2 and survivin as well as upregulaton of pro-apoptotic protein Bax in a time dependent manner when apoptosis ocurred. Ponicidin induced activation of caspase-3 can be blocked by a caspase-3-specific inhibitor z-DEVD-FMK Furthermore, the caspase-8-specific inhibitor z-IETD-FMK could block the ponicidin-induced activation of caspase-3, PARP cleavage, and prevented the release of cytochrome c from mitochondria into the cytoplasm. This indicate that activated caspase-8 initiates the release of cytochrome c during ponicidin-induced apoptosis. We therefore conclude that ponicidin has significant apoptosis-inducing effects by activation of caspase-3 -8, and -9 as well as downregulation of anti-apoptotic protein Bcl-2, survivin and upregulation of pro-apoptotic protein Bax, with caspase-8 acting as an upstream activator. The data offer a potential mechanism for ponicidin-induced apoptosis in lung cancer cells, suggesting that ponicidin may severve as an effective reagent for the treatment of lung cancer, and that in vivo anti-cancer effects as well as its potential clinical effectiveness need further investigation.
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PMID:Ponicidin, an ent-kaurane diterpenoid derived from a constituent of the herbal supplement PC-SPES, Rabdosia rubescens, induces apoptosis by activation of caspase-3 and mitochondrial events in lung cancer cells in vitro. 1653 82

The present study examined the possibility to enhance lung cancer cell cytotoxicity and apoptosis of the anticancer drug cisplatin by exposure with adenylate cyclase (AC) toxin from Bordetella pertussis. A malignant mesothelioma cell line (P31) and a small-cell lung cancer cell line (U1690) were exposed to increasing concentrations of cisplatin and AC toxin, alone or in combination. Cytotoxicity was determined by a fluorescein-based assay and apoptosis by flow cytometry quantification of annexin V binding. Caspase-3, -8, and -9 activities were measured by enzyme activity assays. The cytotoxicity of AC toxin was time and dose dependent with an LD50 value at 72 h of 3 and 7 mg/L for P31 cells and U1690 cells, respectively. Cisplatin showed a similar time- and dose-dependent cytotoxicity, which was increased in the presence of a low toxic concentration (1 mg/L) of AC toxin. Furthermore, cisplatin caused a dose-dependent increase of annexin V binding cells of both cell lines after 24-h incubation, which was also enhanced in combination with AC toxin. AC toxin (1 mg/L) increased cisplatin-induced caspase-3, -8, and -9 activities in U1690 cells. Only minor increases of caspase-8 and -9 were noted for P31 cells. The present results, together with the knowledge that bacterial toxins decrease side effects of traditional cancer treatment, suggest a possibility to use them to enhance the therapeutic effect of cancer chemotherapy with reduced clinical adverse effects.
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PMID:Adenylate cyclase toxin from Bordetella pertussis enhances cisplatin-induced apoptosis to lung cancer cells in vitro. 1655 48


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