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)

Deletion at chromosome 3p21.3 is the earliest and the most frequently observed genetic alteration in lung cancer, suggesting that the region contains tumor suppressor gene(s) (TSG). Identification of those genes may lead to the development both of biomarkers to identify high-risk individuals and novel therapeutics. Previously, we cloned the H37/Luca15/RBM5 gene from 3p21.3 and showed its TSG characteristics. To investigate the physiologic function of H37 in the lung and its mechanism of tumor suppression, we have stably transfected H37 into A549 non-small cell lung cancer cells. A549/H37 cells show significant growth inhibition compared with the vector controls by in vitro and in vivo cell proliferation assays. Using this lung cancer cell model, we have found that the molecular mechanism of H37 tumor suppression involves both cell cycle (G(1)) arrest and apoptosis. To further define H37's function in cell cycle/apoptotic pathways, we investigated differential expression profiles of various cell cycle and apoptosis regulatory proteins using Western blot analysis. Both cyclin A and phophorylated RB levels were decreased in H37-transfected cells, whereas expression of Bax protein was increased. Mitochondrial regulation of apoptosis further downstream of Bax was investigated, showing change in the mitochondrial membrane potential, cytochrome c release into the cytosol, and enhanced caspase-9 and caspase-3 activities. We also report that H37 may mediate apoptosis in a p53-independent manner, and Bax knockdown by small interfering RNA suggests Bax plays a functional role downstream of H37. Lastly, we proposed a tumor suppression model of H37 as a post-transcriptional regulator for cell cycle/apoptotic-related proteins.
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PMID:3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. 1658 63

A variety of melanoma antigen A (MAGE-A) genes are commonly detected in non-small cell lung cancers. Their biological function is not well characterized but may involve the regulation of apoptosis and cell cycle progression. We hypothesized that MAGE-A4 is involved in the regulation of apoptosis. To investigate this, expression of MAGE-A was evaluated. MAGE-A4 was expressed in 48% of non-small cell lung carcinomas. Ninety percent of lung carcinomas expressing MAGE-A4 were classified as squamous cell carcinomas and 10% were adenocarcinomas. Tumor-free surrounding lung tissue was negative for MAGE-A4. A molecular clone of MAGE-A4 derived from human lung cancer was stably expressed in human embryonic kidney cells (293 cells) to evaluate effects on cell death. Overexpression of MAGE-A4 increased apoptosis as measured by the apoptotic index (P < 0.0001) and caspase-3 activity (P < 0.002). Exposure to 25 micromol/L etoposide, a chemotherapeutic agent, increased the apoptotic effect (P < 0.0001). Furthermore, we show that MAGE-A4 silencing using a small interfering RNA approach results in decreased caspase-3 activity in the squamous cell lung cancer cell line H1703 by 58% (P = 0.0027) and by 24% (P = 0.028) in 293/MAGE-A4 cells. These findings suggest that MAGE-A4 expression may promote tumor cell death, sensitize malignancies to apoptotic stimuli, such as chemotherapeutic agents, and therefore may represent a tumor suppressor protein.
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PMID:Melanoma antigen A4 is expressed in non-small cell lung cancers and promotes apoptosis. 1665 21

Non-steroidal anti-inflammatory drugs (NSAIDs) are known to enhance the responsiveness of tumor cells toward chemotherapeutic drugs and radiation. However, the precise mechanism of synergistic enhancement in tumoricidal activity is not clearly known. Herein, we demonstrate that the combination treatment of arsenic trioxide (As2O3) and sulindac resulted in a synergistic augmentation of cytotoxicity toward NCI-H157 lung cancer cells, which was revealed as apoptosis accompanied by chromatin fragmentation and an increase in sub-G0/G1 fraction. In addition, combination treatment with As2O3 and sulindac increased the catalytic activity of caspase-3, -8, and -9 along with induction of Fas/FasL expression and cytosolic release of cytochrome c. Pharmacologic scavenging study of reactive oxygen species (ROS) revealed that synergistic augmentation of cytotoxicity was achieved by generation of ROS, which might modulate the expression of Bcl-2 family proteins, the activity of caspase-3, and mitochondrial membrane potential transition.
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PMID:Combination treatment with arsenic trioxide and sulindac augments their apoptotic potential in lung cancer cells through activation of caspase cascade and mitochondrial dysfunction. 1668 42

Pseudolaric acid-B (PLAB), a diterpene acid, was isolated from the root and trunk barks of Pseudolarix kaempferi. It showed antifungal and anti-fertility effects as well as cytotoxic activities in previous studies. The present study investigates cytotoxic activity on cultured human cancer cells, inhibition on the growth of transplantable tumours in mice and the mechanism of these actions. The experimental results showed that PLAB had potent cytotoxic effects on cancer cells derived from different tissues. MTT assay showed that its IC50 towards these tumour cells was 0.17 to 5.20 micromol/L, and towards one normal human kidney proximal tubular epithelial cell (HKC) was 5.77 micromol/L. Furthermore, the results of cell growth curve and colony formation of cancer cells matched the above results. The results in vivo demonstrated that PLAB significantly inhibited the growth of transplantable tumours, such as Lewis lung cancer and hepatocarcinoma 22 (H22) in mice. The inhibitory rate to H22 was 14.4% and 40.1%, and to Lewis lung cancer reached 39.1% and 47.0%, when PLAB was given by intraperitoneal injection (i.p.) at a dose of 30 mg/kg/day and 60 mg/kg/day for 10 days, respectively. It is suggested that PLAB also showed obvious anticancer activity in vivo. Inducing apoptosis by PLAB in HeLa cells was assessed by various morphological and biochemical characteristics, including cell shrinkage, chromatin condensation, membrane blebbing, formation of apoptotic bodies, and internucleosomal DNA fragmentation. A typical 'sub-G1 peak' was also checked through flow cytometry. These results were accompanied by up-regulating P53, down-regulating Bcl-2 and activating Caspase-3, which was revealed by Western blotting. PLAB also caused cell cycle arrest to G2/M phase in a dose-dependent manner. The experiments suggest that PLAB is a new potent anti-tumour agent.
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PMID:Studies on anti-tumour activities of pseudolaric acid-B (PLAB) and its mechanism of action. 1686 30

In the treatment of lung cancers, a local cryotherapy can be proposed as a palliative option for bronchial clearance. But this therapy can also be used as an adjuvant treatment, for instance in association with chemotherapy. We have already demonstrated differential biological effects of these therapies and the benefit to combine them. The aim of this study was to determine if this benefit observed at a molecular level was correlated with tumour growth. As vascular changes occur after cryotherapy, intratumoral angiogenesis was also studied. Cells from the A549 cell line were inoculated into SCID mice. Tumours were treated by cryotherapy (nitrous oxide cryoprobe), chemotherapy (injection of Vinorelbine) or both. Tumour growth was studied in each group and the T/C ratios were compared. Tumours treated by cryochemotherapy presented a significantly reduced volume and the lower T/C ratio, confirming the benefit of a combined treatment. Angiogenesis was assessed at variable time points after cryotherapy by immunohistochemical staining of VEGF and western blot analysis. A late cryo-induced angiogenesis was observed 8-15 days after treatment (expression of VEGF increased from 13% in untreated tumours to 77 and 70%, respectively). To determine if this hypervascularization could enhance the efficiency of chemotherapy, the drug was injected 15 days after cryotherapy and the induction of cell death was investigated (morphological study, immunohistochemical staining of cleaved caspase-3, TUNEL). Necrosis was increased but not apoptosis, suggesting that though a crucial parameter, intratumoral microvessel density is not the only factor to consider to reach an optimal efficiency of a combined treatment.
Lung Cancer 2006 Oct
PMID:Benefit of a combined treatment of cryotherapy and chemotherapy on tumour growth and late cryo-induced angiogenesis in a non-small-cell lung cancer model. 1688 70

Ganoderma lucidum is a well-known traditional Chinese medicinal herb containing many bioactive compounds. Ganoderic acid T (GA-T), which is a lanostane triterpenoid purified from methanol extract of G. lucidum mycelia, was found to exert cytotoxicity on various human carcinoma cell lines in a dose-dependent manner, while it was less toxic to normal human cell lines. Animal experiments in vivo also showed that GA-T suppressed the growth of human solid tumor in athymic mice. It markedly inhibited the proliferation of a highly metastatic lung cancer cell line (95-D) by apoptosis induction and cell cycle arrest at G(1) phase. Moreover, reduction of mitochondria membrane potential (Delta psi(m)) and release of cytochrome c were observed during the induced apoptosis. Our data further indicate that the expression of proteins p53 and Bax in 95-D cells was increased in a time-dependent manner, whereas the expression of Bcl-2 was not significantly changed; thus the ratio of Bcl-2/Bax was decreased. The results show that the apoptosis induction of GA-T was mediated by mitochondrial dysfunctions. Furthermore, stimulation of the activity of caspase-3 but not caspase-8 was observed during apoptosis. The experiments using inhibitors of caspases (Z-VAD-FMK, Z-DEVD-FMK and Z-IETD-FMK) confirmed that caspase-3 was involved in the apoptosis. All our findings demonstrate that GA-T induced apoptosis of metastatic lung tumor cells through intrinsic pathway related to mitochondrial dysfunction and p53 expression, and it may be a potentially useful chemotherapeutic agent.
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PMID:Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells. 1700 87

Celecoxib is being evaluated as a chemopreventive agent. However, its mechanism of action is not clear because high doses were used for in vitro studies to obtain antitumor effects. We found that celecoxib inhibited the growth of premalignant and malignant human bronchial epithelial cells with IC(50) values between 8.9 and 32.7 micromol/L, irrespective of cyclooxygenase-2 (COX-2) expression. Normal human bronchial epithelial cells were less sensitive to celecoxib. Because these concentrations were higher than those attainable in vivo (<or=5.6 micromol/L), we surmised that combining celecoxib with the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR) might improve its efficacy. Treatment of premalignant lung cell lines with combinations of clinically relevant concentrations of celecoxib (<or=5 micromol/L) and 4HPR (<or=0.25 micromol/L) resulted in greater growth inhibition, apoptosis induction, and suppression of colony formation than did either agent alone. This combination also decreased the levels of Bcl-2, induced the release of mitochondrial cytochrome c, activated caspase-9 and caspase-3, and induced cleavage of poly(ADP-ribose)polymerase at concentrations at which each agent alone showed no or minimal effects. Furthermore, combinations of celecoxib and 4HPR suppressed the phosphorylation levels of serine/threonine kinase Akt and its substrate glycogen synthase kinase-3beta more effectively than the single agents did. Accordingly, overexpression of constitutively active Akt protected bronchial epithelial cells from undergoing apoptosis after incubation with both celecoxib and 4HPR. These findings indicate that activation of the mitochondrial apoptosis pathway and suppression of the Akt survival pathway mediate the augmented apoptosis and suggest that this combination may be useful for lung cancer chemoprevention.
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PMID:Involvement of mitochondrial and Akt signaling pathways in augmented apoptosis induced by a combination of low doses of celecoxib and N-(4-hydroxyphenyl) retinamide in premalignant human bronchial epithelial cells. 1701 36

Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm(3)); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16(INKa), Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses.
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PMID:Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity. 1701 11

15-Deoxy-Delta-prostaglandin J2 is a naturally occurring endogenous ligand for peroxisome proliferator-activated receptor-gamma. The current study was aimed to determine the mechanism of anti-proliferative effect of 15-deoxy-Delta-prostaglandin J2+docetaxel against A549 and H460 non-small-cell lung cancer cell lines and xenograft tumors. In-vitro cytotoxicity of 15-deoxy-Delta-prostaglandin J2 alone and in combination with docetaxel was studied against A549 and H460 cell lines. For in-vivo studies, female athymic nu/nu mice were xenografted with A549 and H460 tumors and treated with 15-deoxy-Delta-prostaglandin J2 (1 mg/kg/day; intraperitoneal), docetaxel (10 mg/kg; intravenous on days 14, 18 and 22) and 15-deoxy-Delta-prostaglandin J2+docetaxel. Apoptosis was measured in A549 cells and tumor tissues, following various treatments. Peroxisome proliferator-activated receptor-gamma, caspases, Bcl2 and p53 family proteins or their mRNA expressions were measured by Western blotting, reverse transcription-polymerase chain reaction and real-time polymerase chain reaction in A549 tumors. A possible role of a peroxisome proliferator-activated receptor-gamma-independent mechanism was studied in A549 cells treated with peroxisome proliferator-activated receptor-gamma antagonist, GW9662. Isobolographic analysis demonstrated synergistic interaction (combination index <1.0) between 15-deoxy-Delta-prostaglandin J2 and docetaxel against A549 and H460 cells in vitro. 15-Deoxy-Delta-prostaglandin J2+docetaxel significantly reduced the tumor volume compared with control (P<0.05), 15-deoxy-Delta-prostaglandin J2 (P<0.05) and docetaxel (P<0.05, P<0.01) in both A549 and H460 tumors. 15-Deoxy-Delta-prostaglandin J2+docetaxel showed a significant increase in apoptosis associated with inhibition of the Bcl2 and cyclin D1 expression and overexpression of caspase and p53 pathway genes. Further, enhanced expression of caspase 3 and inhibition of cyclin D1 by 15-deoxy-Delta-prostaglandin J2+docetaxel was not reversed by GW9662, thus suggesting a possible peroxisome proliferator-activated receptor-gamma-independent mechanism. In conclusion, 15-deoxy-Delta-prostaglandin J2 enhanced the anti-tumor action of docetaxel by peroxisome proliferator-activated receptor-gamma-dependent and -independent mechanisms mediated by induction of apoptosis.
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PMID:15-Deoxy-Delta12,14-prostaglandin J2 enhances docetaxel anti-tumor activity against A549 and H460 non-small-cell lung cancer cell lines and xenograft tumors. 1715 4

The jasmonates, cis-jasmone (CJ) and methyl jasmonate (MJ), were investigated for their effects against NSCLC cell lines A549 and H520. CJ or MJ inhibited the proliferation of both cell lines in a dose-dependent manner as well as induced cell cycle arrest in the G2/M phase. Apoptosis was observed following treatment with CJ or MJ as indicated by Hoechst staining and confirmed by dual annexin V-fluorescein isothiocyanate (FITC)/prodium iodide (PI) and DAPI (4',6-diamidine-2'-phenylindole dihydrochloride) staining. p38 and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation was observed with increased expression of bax, p21, and caspase-3 activity. These observations indicate that jasmonates may have a therapeutic value in the treatment of lung cancer.
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PMID:Jasmonates induce apoptosis and cell cycle arrest in non-small cell lung cancer lines. 1716 56


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