UMLS:C0242379 - FACTA Search

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

Honokiol is a phenolic compound purified from Magnolia officinalis, which induced the apoptotic cell death in several types of human cancer cells. In the present study, the molecular mechanism of honokiol-mediated apoptotic process was examined in human squamous lung cancer CH27 cells. Here, we found that honokiol-induced apoptotic cell death was accompanied by upregulation of Bad and downregulation of Bcl-XL, while honokiol had no effect on the levels of Bcl-2, Bcl-XS, Bag-1, Bax and Bak proteins. Moreover, honokiol treatment caused the release of mitochondrial cytochrome c to cytosol and sequential activation of caspases. Proteolytic activation of caspase-3 and cleavage of PARP, an in vivo substrate for caspase-3, were observed in honokiol-treated CH27 cells. Furthermore, treatment with caspase inhibitors z-DEVD-fmk and z-VAD-fmk markedly blocked honokiol-induced apoptosis. These results demonstrated that modulation of Bcl-XL and Bad proteins, release of mitochondrial cytochrome c and activation of caspase-3, participated in honokiol-triggered apoptotic process in human squamous lung cancer CH27 cells.
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PMID:Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells. 1200 67

The present study examined whether X-ray- and CDDP-sensitivities depend on p53 gene status in human squamous cell carcinoma of the head and neck (SAS cells) showing dominant negative nature of mutant p53 protein. SAS cells were transfected with a vector carrying a mutant p53 gene (SAS/Trp248 cells) or neomycin resistant gene control vector (SAS/neo cells). Sensitivities of the transfected cells to X-ray or CDDP were measured with colony formation assay. The incidence of apoptosis by X-ray or CDDP was analyzed with Hoechst staining or DNA ladder formation assay. The activation of caspase-3 was estimated as an indicator of apoptosis by the detection of fragmentation of caspase-3 or poly (ADP ribose) polymerase (PARP) with Western blot. SAS/Trp248 cells showed X-ray- and CDDP-resistance due to the dominant negative nature of mutant p53, compared with SAS/neo cells. The incidence of DNA ladders and apoptotic bodies increased markedly in SAS/neo cells after X-ray irradiation or CDDP treatment, but increased only slightly in SAS/Trp248 cells. Fragmentation of caspase-3 and PARP was observed in SAS/neo cells, but almost no such fragmentation was observed in SAS/Trp248 cells after X-ray irradiation or CDDP treatment. The present results strongly suggest that the X-ray- and CDDP-sensitivities of human squamous cell carcinomas are p53-dependent, and that the sensitivities are tightly correlated with the induction of apoptosis through caspase-3 activation. The p53-dependent X-ray- or CDDP-sensitivity was supported by results from p53-null human lung cancer H1299 cells which were transfected with wild-type or mutant p53 gene.
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PMID:Transfection of mutant p53 gene depresses X-ray- or CDDP-induced apoptosis in a human squamous cell carcinoma of the head and neck. 1210 96

The serine/threonine protein kinase C (PKC) has been implicated in the regulation of drug resistance and cell survival in many types of cancer cells. However, the one or more precise mechanisms remain elusive. In this study, we have identified and determined the mechanism by which PKC-epsilon, a novel PKC isoform, modulates drug resistance in lung cancer cells. Western blot analysis demonstrates that expression of PKC-epsilon, but not other PKC isoforms, is associated with the chemo-resistant phenotype of non-small cell lung cancer (NSCLC) cell lines. Northern blotting and nuclear run-on transcription analysis further reveals that the failure of expression of PKC-epsilon in the chemo-sensitive phenotype of small cell lung cancer (SCLC) cells results from transcriptional inactivation of the gene. Importantly, forced expression of PKC-epsilon in NCI-H82 human SCLC cells confers a significant resistance to the chemotherapeutic drugs, etoposide and doxorubicin. Resistance is characterized by a significant reduction in apoptosis in PKC-epsilon-expressing cells. Treatment of NCI-H82 cells with etoposide induces a series of time-dependent events, including the release of cytochrome c from the mitochondria to the cytosol, activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). All of these events are blocked by PKC-epsilon expression. Furthermore, caspase-specific inhibitors, z-VAD-fmk and z-DEVD-fmk, significantly attenuate the accumulation of sub-G(1) population and block the PARP cleavage in response to etoposide. These results suggest that PKC-epsilon prevents cells from undergoing apoptosis through inhibition of the mitochondrial-dependent caspase activation, thereby leading to cell survival. Finally, down-regulation of PKC-epsilon expression by the antisense cDNA in NSCLC cells results in increased sensitivity to etoposide. Taken together, our findings suggest an important role for PKC-epsilon in regulating survival of lung cancer cells.
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PMID:Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. 1212 73

Arsenic trioxide (As(2)O(3)) has been found to induce apoptosis in leukemia cell lines and clinical remissions in patients with acute promyelocytic leukemia. In this study, we investigated the cytotoxic effect and mechanisms of action of As(2)O(3) in human tumor cell lines. As(2)O(3) caused inhibition of cell growth (IC(50) range, 3-14 microM) in a variety of human solid tumor cell lines, including four human non-small-cell lung cancer cell lines (H460, H322, H520, H661), two ovarian cancer cell lines (SK-OV-03, A2780), cervical cancer HeLa, and breast carcinoma MCF-7, as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry analysis showed that As(2)O(3) treatment resulted in a time-dependent accumulation of cells in the G(2)/M phase. We observed, using Wright-Giemsa and 4',6-diamidine-2-phenylindole-dihydrochloride staining, that As(2)O(3) blocked the cell cycle in mitosis. In vitro examination revealed that As(2)O(3) markedly promoted tubulin polymerization without affecting GTP binding to beta-tubulin. Immunocytochemical and EM studies of treated MCF-7 cells showed that As(2)O(3) treatment caused changes in the cellular microtubule network and formation of polymerized microtubules. Similar to most anti-tubulin agents, As(2)O(3) treatment induced up-regulation of the cyclin B1 levels and activation of p34(cdc2)/cyclinB1 kinase, as well as Bcl-2 phosphorylation. Furthermore, activation of caspase-3 and -7 and cleavage of poly(ADP-ribose) polymerase and beta-catenin occurred only in As(2)O(3)-induced mitotic cells, not in interphase cells, suggesting that As(2)O(3)-induced mitotic arrest may be a requirement for the activation of apoptotic pathways. In addition, As(2)O(3) exhibited similar inhibitory effects against parental MCF-7, P-glycoprotein-overexpressing MCF-7/doxorubicin cells, and multidrug resistance protein (MRP)-expressing MCF-7/etoposide cells (resistance indices, 2.3 and 1.9, respectively). Similarly, As(2)O(3) had similar inhibitory effect against parental ovarian carcinoma A2780 cells and tubulin mutation paclitaxel-resistant cell lines PTx10 and PTx22 (resistance indices, 0.86 and 0.93, respectively), suggesting that its effect on tubulin polymerization and G(2)/M phase arrest is distinct from that of paclitaxel. Taken together, our data demonstrate that As(2)O(3) has a paclitaxel-like effect, markedly promotes tubulin polymerization, arrests cell cycle at mitosis, and induces apoptosis. In addition, As(2)O(3) is a poor substrate for transport by P-glycoprotein and MRP, and non-cross-resistant with paclitaxel resistant cell lines due to tubulin mutation, suggesting that As(2)O(3) may be useful for treatment of human solid tumors, particularly in patients with paclitaxel resistance.
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PMID:Arsenic trioxide produces polymerization of microtubules and mitotic arrest before apoptosis in human tumor cell lines. 1218 29

Recent study indicated that the components of Toona sinensis Roemor have potent anti-inflammatory and analgesic effects. These components have also been reported to inhibit the growth of boils in vivo. In this study, we investigated the effect of crude extract from the leaves of Toona sinensis Roemor on the proliferation of A549 lung cancer cells. We found that the extract effectively blocked cell cycle progression by inhibiting the expression of cyclin D1 and E in A549 cells. Additionally, incubation of the extract led to activation of caspase-3-like proteases and apoptotic cell death. Conversely, the extract did not show any significant cytotoxic effect on primarily cultured human foreskin fibroblasts or MRC-5 human lung fibroblasts. Therefore, antiproliferative action of the extract is specific for tumor cells. Our results suggest that the components of Toona sinensis Roemor have potent anticancer effects in vitro and identification of the useful components in the extract may lead to the development of a novel class of anticancer drugs.
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PMID:Extract from the leaves of Toona sinensis roemor exerts potent antiproliferative effect on human lung cancer cells. 1223 19

Lung cancer continues to be the leading cause of cancer-related death in the United States. Therefore, new agents targeting prevention and treatment of lung cancer are urgently needed. In the present study, we demonstrate that a novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) is a potent inducer of apoptosis in human non-small cell lung carcinoma (NSCLC) cells. The concentrations required for a 50% decrease in cell survival (IC50) ranged from 0.1 to 0.3 microM. CDDO-Me induced rapid apoptosis and triggered a series of effects associated with apoptosis including a rapid release of cytochrome c from mitochondria, activation of procaspase-9, -7, -6, and -3, and cleavage of poly(ADP-ribose) polymerase and lamin A/C. Moreover, the caspase-3 inhibitor Z-DEVD-FMK and the pan caspase inhibitor Z-VAD-FMK suppressed CDDO-Me-induced apoptosis. These results indicate that CDDO-Me induced apoptosis in human NSCLC cells via a cytochrome c-triggered caspase activation pathway. CDDO-Me did not alter the level of Bcl-2 and Bcl-xL proteins, and no correlation was found between cell sensitivity to CDDO-Me and basal Bcl-2 expression level. Furthermore, overexpression of Bcl-2 did not protect cells from CDDO-Me-induced apoptosis. These results suggest that CDDO-Me induces apoptosis in NSCLC cells irrespective of Bcl-2 expression level. In addition, no correlation was found between cell sensitivity to CDDO-Me and p53 status, suggesting that CDDO-Me induce a p53-independent apoptosis. Our results demonstrate that CDDO-Me may be a good candidate for additional evaluation as a potential therapeutic agent for human lung cancers and possibly other types of cancer.
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PMID:Identification of a novel synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate, that potently induces caspase-mediated apoptosis in human lung cancer cells. 1246 12

The chronological changes in intracellular Ca(2+)concentrations ([Ca(2+)](i)) were analysed during heat-induced apoptosis in human lung cancer cell lines LK-2 (squamous cell carcinoma) and LU65A (large cell carcinoma). In LK-2 cells, increased [Ca(2+)](i) levels were maintained at levels between 250-350 nm 9 h after heat-shock. Treatment with BAPTA, an intracellular Ca(2+) chelator, prior to heat-shock, decreased the frequency of heat-induced apoptosis in LK-2, while thapsigargin, a selective endoplasmic reticulum Ca(2+)-ATPase inhibitor, did not change the number of apoptotic cells, regardless of the presence or absence of Ca(2+)-supplemented medium. In LU65A cells, treatment with BAPTA or thapsigargin did not alter the apoptotic rates. Western blotting demonstrated that, although expression of Bax and Bcl-2 were not changed by heat-shock, p53 expression was elevated in LK-2, but not LU65A cells. Immunohistochemistry showed that p53 was localized predominantly in the cytoplasms of LK-2 cells, suggesting that p53 protein is not functional in LK-2. Heat-shock also elevated activities of caspase-3, -8 and -9 in both cell lines. It is concluded that a temporal increase in [Ca(2+)](i) is the important initiating factor in hyperthermia-induced apoptosis in LK-2 cells and that, in these two lung cancer cell lines, apoptosis may occur through 'cross-talk' between p53-independent mitochondrial and death receptor pathways.
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PMID:Elevated levels of intracellular Ca2+ and apoptosis in human lung cancer cells given heat-shock. 1262 40

The p53 mutant 143Ala is a human temperature-sensitive mutant with two conformational states. To definitively determine whether the Fas signal transduction pathway and the function of the pathway are dependent on p53 status, we have established stable transfectants of p53 mutant 143Ala in two human cancer cell lines: H1299 (lung cancer line) and PC-3 (prostate cancer line), the native state of which contains null p53 status and can grow at 37 degrees C and 32.5 degrees C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell cycle analysis showed inhibition of the growth of cells overexpressing p53 mutant 143Ala in the wild-type p53 form at 32.5 degrees C because of induction of G0/G1 arrest. Transfected cells had increased protein expression of p21, Fas, and MDM2 at the wild-type p53 conformation at 32.5 degrees C, but not in the mutant p53 form at 37 degrees C. However, there was no change in protein expression of FADD, FAP-1, Bcl-2, or Bax at 32.5 or 37 degrees C. Assays for apoptosis demonstrated that anti-Fas antibody CH-11 and FasL induced apoptosis only in cells that overexpress p53 mutant 143Ala at 32.5 degrees C with the wild-type p53 form. Both caspase-3 and caspase-8 activities were increased by anti-Fas antibody CH-11 only in cells at 32.5 degrees C with wild-type p53. Our results demonstrated that Fas-mediated apoptosis in H1299 and PC-3 cells expressing p53 mutant 143Ala occurred only with the wild-type p53 phenotype. These results support the hypothesis that Fas-mediated apoptosis is dependent, at least partially, on the presence of a functional wild-type p53 state. This model may be a useful tool for dissecting the specific interactions between wild-type p53 and the Fas signal transduction pathway in human cancer cells.
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PMID:Fas-mediated apoptosis is dependent on wild-type p53 status in human cancer cells expressing a temperature-sensitive p53 mutant alanine-143. 1267 Sep

Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer especially in India and displays resistance to anticancer treatment. In our earlier study we had isolated a cDNA clone from rat thymocytes induced to undergo apoptosis, which was found to encode S29 ribosomal protein [Biochem. Biophys. Res. Commun. 277 (2000) 476]. In the present study an attempt has been made to find out whether enhanced expression of S29 cDNA can kill NSCLC H520 cells. We found that S29 induced apoptosis and augmented the effect of anticancer drugs. Expressions of several molecular determinants of apoptosis were analyzed in order to understand the mechanism of apoptosis induced by S29. We observed downregulation of the expression of inhibitors of apoptosis proteins (IAPs) Bcl-2, Bcl-X(L), and survivin and upregulation of pro-apoptotic p53 and Bax as assessed by Western blotting. Mitochondrial release of cytochrome c and activation of initiator caspase-8 and -9 and effector caspase-3, followed by cleavage of nuclear substrate poly(ADP-ribose) polymerase, were also observed. Permeability transition as determined by changes in DeltaPsi(m) was not a requirement for cytochrome c release. There was a marginal increase in the release of apoptosis inducing factor (AIF) and reduction of NF-kappaB dependent transcriptional activity. There was non-involvement of calcium and the telomerase activity, a proliferation marker.
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PMID:S29 ribosomal protein induces apoptosis in H520 cells and sensitizes them to chemotherapy. 1270 79

Phenylacetate is a differentiation agent and has anticancer activity with relatively low toxicity. In the present study, we examined the anticancer effect of six synthetic phenylacetate derivatives in human lung cancer cells in our search for more effective phenylacetate analogous. Results showed that the antiproliferative effects of these synthetic compounds were stronger than those of phenylacetate, and that N-butyl-2-(2-fluorolphenyl)acetamide (SCK6) is the most potent compound. To address the mechanism of the antiproliferative effect of SCK6, cell cycle analysis was performed. Result showed that SCK6 (1 mM) induced G(1) arrest in CH27 cells. Western blot analysis of G(1) phase regulatory proteins demonstrated that the protein levels of cyclin-dependent kinase 2 (Cdk2), Cdk4, Cyclin E and Cyclin D3 were decreased after treatment with SCK6 but not those of Cdk6, Cyclin D1 and D2. In contrast, SCK6 increased the protein levels of p53 and p21(CIP1/WAF1). Data from in situ terminal transferase-mediated dUTP-fluorescensin nick end-labeling (TUNEL) assay and DNA fragmentation analysis demonstrated that SCK6 induced apoptotic cell death in CH27 cells. This SCK6-induced apoptosis was accompanied by a downregulation of Bcl-2 protein and activation of the caspase-9 cascade. Overexpression of Bcl-2 by adeno-Bcl-2 vector infection significantly inhibited SCK6-induced apoptosis. Moreover, treatment with caspase inhibitors also markedly reduced cell death induced by SCK6. Taken together, these results suggest that downregulation of G(1)-associated Cdks and cyclins and upregulation of p53 and p21(CIP1/WAF1) may contribute to SCK6-mediated G(1)-phase arrest. Furthermore, the decrease in Bcl-2 and the activation of caspase-9/caspase-3 may be the effector mechanism through which SCK6 induces apoptosis.
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PMID:A phenylacetate derivative, SCK6, inhibits cell proliferation via G1 cell cycle arrest and apoptosis. 1270 52

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