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)

Irreversible EGFR inhibitors can circumvent acquired resistance to first-generation reversible, ATP-competitive inhibitors in the treatment of non-small-cell lung cancer. They contain both a driver group, which assures target recognition, and a warhead, generally an acrylamide or propargylamide fragment that binds covalently to Cys797 within the kinase domain of EGFR. We performed a systematic exploration of the role for the warhead group, introducing different cysteine-trapping fragments at position 6 of a traditional 4-anilinoquinazoline scaffold. We found that different reactive groups, including epoxyamides (compounds 3-6) and phenoxyacetamides (compounds 7-9), were able to irreversibly inhibit EGFR. In particular, at significant lower concentrations than gefitinib (1), (2R,3R)-N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)oxirane-2-carboxamide (6) inhibited EGFR autophosphorylation and downstream signaling pathways, suppressed proliferation, and induced apoptosis in gefitinib-resistant NSCLC H1975 cells, harboring the T790M mutation in EGFR.
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PMID:Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion. 2015 70

The present study is designed to assess the mitochondrial status during benzo(a)pyrene (B(a)P)-induced lung carcinogenesis in Swiss albino mice and to reveal the modulatory effect of hesperidin over it. B(a)P (50 mg/kg body weight)-induced mitochondrial abnormalities was evident from alterations in mitochondrial lipid peroxides, antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, reduced glutathione, vitamin E, and vitamin C), major tricarboxylic acid (TCA) cycle enzyme activities (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, alpha-ketoglutarate dehydrogenase), electron transport chain (ETC) complexes activities and ATP levels. Ultrastructural changes in lung mitochondria were also in accord with the above aberrations. Hesperidin (25 mg/kg body weight) supplementation effectively counteracted all the above changes and restored cellular normalcy, indicating its protective role during B(a)P-induced lung cancer.
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PMID:Hesperidin attenuates mitochondrial dysfunction during benzo(a)pyrene-induced lung carcinogenesis in mice. 2019 83

The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.
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PMID:Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase. 2042 Mar 87

Otto Warburg's theory on the origins of cancer postulates that tumor cells have defects in mitochondrial oxidative phosphorylation and therefore rely on high levels of aerobic glycolysis as the major source of ATP to fuel cellular proliferation (the Warburg effect). This is in contrast to normal cells, which primarily utilize oxidative phosphorylation for growth and survival. Here we report that the major function of glucose metabolism for Kras-induced anchorage-independent growth, a hallmark of transformed cells, is to support the pentose phosphate pathway. The major function of glycolytic ATP is to support growth under hypoxic conditions. Glutamine conversion into the tricarboxylic acid cycle intermediate alpha-ketoglutarate through glutaminase and alanine aminotransferase is essential for Kras-induced anchorage-independent growth. Mitochondrial metabolism allows for the generation of reactive oxygen species (ROS) which are required for Kras-induced anchorage-independent growth through regulation of the ERK MAPK signaling pathway. We show that the major source of ROS generation required for anchorage-independent growth is the Q(o) site of mitochondrial complex III. Furthermore, disruption of mitochondrial function by loss of the mitochondrial transcription factor A (TFAM) gene reduced tumorigenesis in an oncogenic Kras-driven mouse model of lung cancer. These results demonstrate that mitochondrial metabolism and mitochondrial ROS generation are essential for Kras-induced cell proliferation and tumorigenesis.
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PMID:Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. 2042 86

The aim of this work was to demonstrate the advantage of using paclitaxel (PTX)-loaded Pluronic P123/F127 mixed micelles (PF-PTX) against non-small cell lung cancer (NSCLC) compared to Taxol. Modulation of multidrug resistance (MDR) by Pluronic mixed micelles was evaluated in lung resistance protein (LRP)-overexpressing human lung adenocarcinoma A-549 cell line. Influence of PF-PTX on in vitro cytotoxicity was determined by MTT assay, while cellular apoptosis was detected by cell nuclei staining and Annexin V-FITC apoptosis detection kit. Cell cycle arrest was also confirmed by flow cytometry. Additionally, in vivo fate and antitumor efficacy of PF-PTX were extensively evaluated in comparison with Taxol. It was demonstrated that PF-PTX had superior anti-proliferation activity against A-549 cells compared with Taxol as measured by IC(50). The enhanced anti-cancer efficacy of PF-PTX was associated with PTX-induced apoptosis and cell arrest in the G(2)/M phase. Intracellular ATP depletion and decreased mitochondrial potential caused by Pluronic copolymers were found to be related to modulation of MDR. PF-PTX also exhibited significant advantages in pharmacokinetics and A-549 xenograft tumor model versus Taxol. The PF-PTX formulation achieved 3.0-fold longer mean residence time in circulation, 2.2-fold larger area under the plasma concentration-time curve than Taxol. At 28days, tumor volume in PF-PTX group was only 31.8% that of the Taxol. Therefore, PF-PTX significantly enhanced the anti-cancer activity of PTX and might be considered a promising drug delivery system to overcome MDR in lung cancer.
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PMID:Enhanced antitumor efficacy by paclitaxel-loaded pluronic P123/F127 mixed micelles against non-small cell lung cancer based on passive tumor targeting and modulation of drug resistance. 2045 5

Arsenic is a heavy metal that is ubiquitous in the environment. The toxicity of arsenic depends upon its chemical form; the organic forms being usually less harmful than inorganic ones. The primary source of human exposure is through drinking water and food. Arsenic acts on cells through a variety of mechanisms, influencing numerous signal transduction pathways and resulting in a vast range of cellular effects that include apoptosis induction, growth inhibition, promotion or inhibition of differentiation, and angiogenesis inhibition. The primary objective of this research is to evaluate the effects of arsenic trioxide on DNA synthesis and to determine whether arsenic induces apoptosis via caspase activation and the activation the mitogen -activated protein kinase (MAPK) in lung carcinoma cells. To achieve this goal, the lung cancer (A549) cells were cultured following standard protocols, and exposed to various doses (0, 2, 4, 6, 8, and 10 mug/ml) of arsenic trioxide for 48 h with LC(50) being 7.8mug/ml. The proliferative response (DNA synthesis) to arsenic trioxide was determined by [(3)H] thymidine incorporation assay. Arsenic trioxide-induced apoptosis was determined by DNA laddering. Caspase -3 activation was assessed by the caspase-3 fluorescein isothiocyanate (FITC) assay. p38 MAP kinase activity was examined by immunoblot analysis using phospho p38 MAPK mab primary antibody in the presence of ATP and transcription factor (ATF-2) as a substrate. [(3)H] thymidine incorporation assay revealed biphasic reaction; showing cell proliferation at a lower level of exposure, and a dose-related cytotoxic response at higher levels of exposure in A549 cell line. Findings from the DNA laddering assay indicated that arsenic trioxide induced apoptosis in the lung carcinoma cells. Our findings revealed that arsenic trioxide modulated caspase 3 activity and induced p38 map kinase activation in lung carcinoma (A549) cells.
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PMID:Arsenic Trioxide Modulates DNA Synthesis and Apoptosis in Lung Carcinoma Cells. 2045 3

Although the role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has been most extensively studied in hematopoietic cells and hematologic malignancies, it is also activated in epithelial tumors, including those originating in the lungs and head and neck. The canonical pathway involves the activation of JAK following ligand binding to cytokine receptors. The activated JAKs then phosphorylate STAT proteins, leading to their dimerization and translocation into the nucleus. In the nucleus, STATs act as transcription factors with pleiotropic downstream effects. STATs can be activated independently of JAKs, most notably by c-Src kinases. In cancer cells, STAT3 and STAT5 activation leads to the increased expression of downstream target genes, leading to increased cell proliferation, cell survival, angiogenesis, and immune system evasion. STAT3 and STAT5 are expressed and activated in head and neck squamous cell carcinoma (HNSCC) where they contribute to cell survival and proliferation. In HNSCC, STATs can be activated by a number of signal transduction pathways, including the epidermal growth factor receptor (EGFR), alpha7 nicotinic receptor, interleukin (IL) receptor, and erythropoietin receptor pathways. Activated STATs are also expressed in lung cancer, but the biological effects of JAK/STAT inhibition in this cancer are variable. In lung cancer, STAT3 can be activated by multiple pathways, including EGFR. Several approaches have been used to inhibit STAT3 in the hopes of developing an antitumor agent. Although several STAT3-specific agents are promising, none are in clinical development, mostly because of drug delivery and stability issues. In contrast, several JAK inhibitors are in clinical development. These orally available, ATP-competitive, small-molecule kinase inhibitors are being tested in myeloproliferative disorders. Future studies will determine whether JAK inhibitors are useful in the treatment of HNSCC or lung cancer.
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PMID:Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. 2047 3

Adenosine 5'-triphosphate (ATP) plays an important role in nociceptive processing. We used a mouse model of skin cancer pain to investigate the role of ATP in cancer pain. Orthotopic inoculation of B16-BL6 melanoma cells into the hind paw produced spontaneous licking of the tumor-bearing paw. Intraperitoneal injection of the P2 purinoceptor antagonist suramin suppressed spontaneous licking dose-dependently. Two P2X purinoceptor antagonists also suppressed spontaneous licking. An intraplantar injection of ATP, which did not induce licking in the healthy paw, increased licking of the tumor-bearing paw. Spontaneous firing of the tibial nerve was significantly increased in tumor-bearing mice and was inhibited by suramin. Extracellular concentration of ATP was significantly increased in the tumor-bearing paw than in the normal paw. ATP is concentrated in the culture medium of melanoma, lung cancer and breast cancer cells, but not fibroblasts. The P2X(3) receptor was expressed in about 40% of peripherin-positive small and medium-sized neurons in the dorsal root ganglia. P2X(3)-positive neurons were significantly increased in melanoma-bearing mice. These results suggest that ATP and P2X, especially P2X(3), receptors are involved in skin cancer pain, due to the increased release of ATP and increased expression of P2X(3) receptors in the sensory neurons.
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PMID:Involvement of peripheral adenosine 5'-triphosphate and P2X purinoceptor in pain-related behavior produced by orthotopic melanoma inoculation in mice. 2052 75

Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and have poor long-term prognosis. Gefitinib, a targeted therapy that prevents ATP binding in the tyrosine kinase domain of the EGF receptor, has been subject to comprehensive clinical development. A Phase III trial has demonstrated that gefitinib is superior to carboplatin/paclitaxel in terms of progression-free survival and objective response rate, as first-line treatment for pulmonary adenocarcinoma among never-smokers or former light smokers in East Asia (the IRESSA Pan-Asia Study), with the presence of an EGFR mutation being a strong predictor of the effect of gefitinib compared with carboplatin/paclitaxel. In this article, these results are discussed in the context of other recently reported studies of EGFR mutation-positive patients in both Asian and non-Asian countries. Furthermore, the clinical implications and future challenges for gefitinib are highlighted.
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PMID:A major step towards individualized therapy of lung cancer with gefitinib: the IPASS trial and beyond. 2055 17

We examined the effects of transforming growth factor beta(1) (TGFbeta(1)) on cellular functions in human lung cancer cell line A549. Treatment of A549 cells with 1 ng/ml TGFbeta(1) for more than 3 days altered their morphology from an epithelial cobblestone-like appearance to a fibroblast-like one, reduced the expression of E-cadherin mRNA and protein, and induced the formation of F-actin fibers. These hallmarks indicate that TGFbeta(1) induced the epithelial-mesenchymal transition in A549 cells. Migration of TGFbeta(1)-treated A549 cells, which was quantified by the wound-healing assay, was markedly accelerated by 3 microM ATPgammaS, a non-hydrolyzable ATP analogue. ATPgammaS-induced migration of TGFbeta(1)-treated A549 cells was reversed by the P2 antagonist suramin. In contrast, migration of control A549 cells was not altered by ATPgammaS. TGFbeta(1)-treated A549 cells showed an augmentation of ATP-induced Ca(2+) transients, thapsigargin-induced Ca(2+) transients, and store-operated Ca(2+) entry compared with those in control cells. Basal level of the extracellular ATP concentration was significantly lower in TGFbeta(1)-treated A549 cells than in control cells. We conclude from these results that TGFbeta(1) augments ATP-induced Ca(2+) mobilization, which leads to the acceleration of migration, in A549 cells but, it markedly reduces endogenous ATP release. This implies that the actions of ATP would become a novel therapeutic target for inhibiting cancer cell migration.
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PMID:Transforming growth factor beta1 alters calcium mobilizing properties and endogenous ATP release in A549 cells: possible implications for cell migration. 2066 65


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