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)

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

Arsenic is an effective therapeutic agent for the treatment of patients with refractory or relapsed acute promyelocytic leukemia. The use of arsenic for treating solid tumors, particularly in combination with other chemotherapeutic agents, has been extensively studied. Here, we report that arsenite-resistant human lung cancer CL3R15 cells constitutively overexpress NAD(P)H quinone oxidoreductase 1 (NQO1), an enzyme responsible for activation of mitomycin C (MMC), and are more susceptible to MMC cytotoxicity than parental CL3 cells. The effects of arsenite pretreatment on NQO1 induction were examined in CL3, H1299, H460, and MC-T2 cells. Arsenite pretreatment significantly enhanced the expression of NQO1 and susceptibility to MMC in CL3, H1299, and MC-T2 cells, but not in H460 cells that express high endogenous levels of NQO1. Alternatively, arsenic pretreatment reduced adriamycin sensitivity of CL3 cells. Arsenite-mediated MMC susceptibility was abrogated by dicumarol (DIC), an NQO1 inhibitor, indicating that NQO1 is one of the key regulators of arsenite-mediated MMC susceptibility. Various cancer cell lines showed different basal levels of NQO1 activity and a different capacity for NQO1 induction in response to arsenite treatment. However, overall, there was a positive correlation between induced NQO1 activity and MMC susceptibility in cells pretreated with various doses of arsenite. These results suggest that arsenite may increase NQO1 activity and thus enhance the antineoplastic activity of MMC. In addition, our results also showed that inhibition of NQO1 activity by DIC reversed the arsenite resistance of CL3R15 cells.
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PMID:Arsenite pretreatment enhances the cytotoxicity of mitomycin C in human cancer cell lines via increased NAD(P)H quinone oxidoreductase 1 expression. 1649 10

Arsenite is a well known metalloid human carcinogen, and epidemiological evidence has demonstrated its association with the increased incidence of lung cancer. However, the mechanism involved in its lung carcinogenic effect remains obscure. The current study demonstrated that exposure of human bronchial epithelial cells (Beas-2B) to arsenite resulted in a marked induction of cyclooxygenase (COX)-2, an important mediator for inflammation and tumor promotion. Exposure of the Beas-2B cells to arsenite also led to significant transactivation of nuclear factor of activated T-cells (NFAT), but not activator protein-1 (AP-1) and NFkappaB, suggesting that NFAT, rather than AP-1 or NFkappaB, is implicated in the responses of Beas-2B cells to arsenite exposure. Furthermore, we found that inhibition of the NFAT pathway by either chemical inhibitors, dominant negative mutants of NFAT, or NFAT3 small interference RNA resulted in the impairment of COX-2 induction and caused cell apoptosis in Beas-2B cells exposed to arsenite. Site-directed mutation of two putative NFAT binding sites between-111 to +65 in the COX-2 promoter region eliminated the COX-2 transcriptional activity induced by arsenite, confirming that those two NFAT binding sites in the COX-2 promoter region are critical for COX-2 induction by arsenite. Moreover, knockdown of COX-2 expression by COX-2-specific small interference RNA also led to an increased cell apoptosis in Beas-2B cells upon arsenite exposure. Together, our results demonstrate that COX-2 induction by arsenite is through NFAT3-dependent and AP-1- or NFkappaB-independent pathways and plays a crucial role in antagonizing arsenite-induced cell apoptosis in human bronchial epithelial Beas-2B cells.
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PMID:Cyclooxygenase-2 induction by arsenite is through a nuclear factor of activated T-cell-dependent pathway and plays an antiapoptotic role in Beas-2B cells. 3154 Oct 29

Arsenic trioxide (ATO) affects many biological processes such as cell proliferation, apoptosis, differentiation and angiogenesis. L-buthionine sulfoximine (BSO) is an inhibitor of GSH synthesis. We tested whether ATO reduced the viability of lung cancer A549 cells in vitro, and investigated the in vitro effect of the combination of ATO and BSO on cell viability in relation to apoptosis and the cell cycle. ATO caused a dose-dependant decrease of viability of A549 cells with an IC50 of more than 50 microM. Low doses of ATO or BSO (1 approximately 10 microM) alone did not induce cell death. However, combined treatment depleted GSH content and induced apoptosis, loss of mitochondrial transmembrane potential (DeltaPsi(m)) and cell cycle arrest in G2. Reactive oxygen species (ROS) increased or decreased depending on the concentration of ATO. In addition, BSO generally increased ROS in ATO-treated A549 cells. ROS levels were at least in part related to apoptosis in cells treated with ATO and/or BSO. In conclusion, we have demonstrated that A549 lung cells are very resistant to ATO, and that BSO synergizes with clinically achievable concentration of ATO. Our results suggest that combination treatment with ATO and BSO may be useful for treating lung cancer.
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PMID:Induction of apoptosis in arsenic trioxide-treated lung cancer A549 cells by buthionine sulfoximine. 1859 14

Arsenic trioxide (As2O3) has been introduced to the treatment of acute promyelocytic leukemia (APL), and has also been shown to induce apoptosis in a variety of solid tumor cell lines, including non-small cell lung cancer. However, the prohibitively high concentration required for the induction of apoptotic cell death in many solid tumor cells is unacceptable for clinical utilization due to the excessive toxicity associated with this dose. Sulindac is known to enhance the cellular responsiveness of tumors toward chemotherapeutic drugs. Herein, we demonstrated that combination treatment with As2O3 and sulindac resulted in a synergistic augmentation of cytotoxicity in H157 lung cancer cells, which was revealed by apoptotic induction as demonstrated by an increase in the sub-G0/G1 fraction. In addition, combination treatment with As2O3 and sulindac increased reactive oxygen species (ROS) and oxidative stress, as evidenced by the heme oxygenase-1 (HO-1) expression and mitogen-activated protein kinase (MAPK) phosphorylation. MAPK inhibitors blocked the induction of HO-1 by combination treatment. Inhibitors of p38 and JNK partially inhibited the augmented cell death whereas the ERK inhibitor showed poor inhibition. Combination treatment with As2O3 and sulindac induced oxidative DNA damage in a time-dependent fashion, which was evaluated by H2AX phosphorylation along with HO-1 induction.
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PMID:Combination treatment with arsenic trioxide and sulindac enhances apoptotic cell death in lung cancer cells via activation of oxidative stress and mitogen-activated protein kinases. 1863 1

Arsenite effects on the benzo[a]pyrene diol epoxide (BPDE)-DNA adduct-induced mutation were evaluated in three human lung cell-lines--A549 (wild-type p53), WI38-VA13 (p53 inhibited by SV40 large-T antigen), and H1299 (p53-null)--by using the pSP189 shuttle vector, which carries a mutation target supF gene. Arsenite alone had no significant effect on the spontaneous supF mutation. BPDE modification of pSP189 enhanced the mutation rates of supF 4.37-fold, 2.96-fold, and 1.95-fold for A549, WI38-VA13, and H1299, respectively. Arsenite potentiated the BPDE-induced mutation rates of supF 2.30-fold, 2.31-fold, and 2.35-fold in A549, WI38-VA13, and H1299, respectively. These results suggest that arsenite potentiates the BPDE-induced supF mutation via a p53-independent mechanism. By using the host cell reactivation assay, we evaluated arsenite effect on repair of BPDE-DNA adducts. We found that the arsenite treatments resulting in relative survival rates 65% had no significant effect on repair of BPDE-DNA adducts, indicating that p53 status did not significantly affect the repair of BPDE-DNA adducts. This study reveals that arsenite enhances the BPDE-DNA adduct-induced mutagenesis with no marked effect on repair of BPDE-DNA adducts, suggesting that arsenic may act as a co-mutagen to promote the development of human lung cancer.
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PMID:Arsenite enhances the benzo[a]pyrene diol epoxide (BPDE)-induced mutagenesis with no marked effect on repair of BPDE-DNA adducts in human lung cells. 1947 Apr 4

Arsenite exposure is associated with an increased risk of human lung cancer. However, the molecular mechanisms underlying the arsenite-induced human lung carcinogenesis remain elusive. In this study, we demonstrated that arsenite upregulates cyclin D1 expression/activity to promote the growth of human bronchial epithelial Beas-2B cells. In this process, the JNKs (c-Jun N-terminal kinases)/c-Jun cascade is elicited. The inhibition of JNKs or c-Jun by chemical or genetic inhibitors blocks the cyclin D1 induction mediated by arsenite. Furthermore, using a loss of function mutant of p85 (Deltap85, a subunit of PI3K) or dominant-negative Akt (DN-Akt), we showed that PI3K and Akt act as the upstream regulators of JNKs and c-Jun in arsenite-mediated growth promotion. Overall, our data suggest a pathway of PI-3K/Akt/JNK/c-Jun/cylin D1 signaling in response to arsenite in human bronchial epithelial cells.
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PMID:PI3K/Akt/JNK/c-Jun signaling pathway is a mediator for arsenite-induced cyclin D1 expression and cell growth in human bronchial epithelial cells. 1951 18

Arsenic trioxide (As(2)O(3)) has been established to be an effective agent for treating acute promyleocytic leukemia. Laboratory data suggest that As(2)O(3) induces apoptosis of several solid tumor cells including lung cancer cells. Regions of tissue hypoxia often arise in aggressive solid tumors, and hypoxic tumors exhibit augmented invasiveness and metastatic ability in several malignancies. Furthermore, hypoxia may impair the treatment efficiency; therefore, we studied the cytotoxic effect of As(2)O(3) on human lung adenocarcinoma cell lines A549 and A549/R (resistant to vincristine, adriamycin and mitomycin etc.) grown under normoxic and hypoxic (1% oxygen) conditions. At both normoxia and hypoxia, 5, 10 and 15 microM As(2)O(3) induced evident growth inhibition and apoptosis in A549 cells as well as A549/R cells after 48 hours of exposure. In contrast, the conventional chemotherapeutic drug vincristine showed lowered efficiency in hypoxic A549 cells. As(2)O(3) induced G(2)/M cell cycle arrest in both normoxic and hypoxic A549 cells. As(2)O(3) significantly decreased the messenger RNA (mRNA) levels of Cyclin B(1) and survivin and the protein levels of Cyclin B(1), phospho-CDC(2) (Thr 161) and survivin in both normoxic and hypoxic A549 cells. Together, our findings indicated that As(2)O(3) significantly inhibited the proliferation of lung cancer cells via G(2)/M cell cycle arrest and induction of apoptosis at both normoxia and hypoxia, and the induction of apoptosis was associated with down regulation of survivin.
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PMID:Arsenic trioxide inhibits the growth of human lung cancer cell lines via cell cycle arrest and induction of apoptosis at both normoxia and hypoxia. 1982 57

Arsenic trioxide (ATO) can regulate many biological functions such as apoptosis and differentiation. We recently demonstrated that ATO-induced apoptosis in Calu-6 lung cancer cells is correlated with glutathione (GSH) content. Here, the effects of ATO and/or mitogen-activated protein kinase (MAPK) inhibitors on Calu-6 cells were investigated in relation to cell growth, cell death, reactive oxygen species (ROS) and GSH levels. Treatment with ATO inhibited the growth of the Calu-6 cells at 72 hours. ATO induced apoptosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). While general nonspecific ROS decreased in the ATO-treated Calu-6 cells, the intracellular superoxide anion (O(2)(-)) level including mitochondrial O(2)(-) increased. ATO also induced GSH depletion in the Calu-6 cells. The treatment with MAP kinase kinase (MEK), c-Jun N-terminal kinase (JNK) and p38 inhibitors intensified the cell growth inhibition, cell death, MMP (DeltaPsi(m)) loss, and GSH depletion in the ATO-treated Calu-6 cells. In addition, the JNK and p38 inhibitors significantly increased the ROS levels including O(2)(-) in the ATO-treated Calu-6 cells. In conclusion, all the MAPK inhibitors slightly intensify cell death in the ATO-treated Calu-6 cells and the changes of ROS and GSH brought about by ATO and/or MAPK inhibitor treatment partially influence cell growth and death in Calu-6 cells.
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PMID:The effect of MAPK inhibitors on arsenic trioxide-treated Calu-6 lung cells in relation to cell death, ROS and GSH levels. 1984 17

Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus an interaction between arsenite and cigarette smoking in lung carcinogenesis was suspected. In the present study, we investigated the interactions of a tobacco-specific carcinogen 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (nicotine-derived nitrosamine ketone, NNK) and arsenite on lung cell transformation. BEAS-2B, an immortalized human lung epithelial cell line, was selected to test the centrosomal abnormalities and colony formation by NNK and arsenite. We found that NNK, alone, could enhance BEAS-2B cell growth at 1-5 microM. Under NNK exposure, arsenite was able to increase centrosomal abnormality as compared with NNK or arsenite treatment alone. NNK treatment could also reduce arsenite-induced G2/M cell cycle arrest and apoptosis, these cellular effects were found to be correlated with p53 dysfunction. Increased anchorage-independent growth (colony formation) of BEAS-2B cells cotreated with NNK and arsenite was also observed in soft agar. Our present investigation demonstrated that NNK could provide a p53 compromised status. Arsenite would act specifically on this p53 compromised status to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenite under tobacco-specific carcinogen co-exposure.
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PMID:Arsenite promotes centrosome abnormalities under a p53 compromised status induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). 1993 52

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