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Novel Compound 1, 3-bis (3, 5-dichlorophenyl) urea Inhibits Lung Cancer Progression.

Biochem Pharmacol. 2013 Oct 4;

Authors: Singhal SS, Figarola J, Singhal J, Nagaprashantha L, Rahbar S, Awasthi S

Abstract
The successful clinical management of lung cancer is limited by frequent loss-of-function mutations in p53 which cooperates with chronic oxidant-stress induced adaptations in mercapturic acid pathway (MAP) which in turn regulates critical intracellular signaling cascades that determine therapeutic refractoriness. Hence, we investigated the anti-cancer effects and mechanisms of action of a novel compound called 1, 3 bis (3, 5-dichlorophenyl) urea (COH-SR4) in lung cancer. Treatment with COH-SR4 effectively inhibited the survival and clonogenic potential along with inducing apoptosis in lung cancer cells. COH-SR4 treatment caused the inhibition of GST activity and G0/G1 cell cycle arrest and inhibited the expression of cell cycle regulatory proteins CDK2, CDK4, cyclin A, cyclin B1, cyclin E1, and p27. The COH-SR4 activated AMPK pathway and knock-down of AMPK partially reversed the cytotoxic effects of COH-SR4 in lung cancer. COH-SR4 treatment lead to regression of established xenografts of H358 lung cancer cells without any overt toxicity. The histopathology of resected tumor sections revealed an increase in pAMPK, a decrease in the nuclear proliferative marker Ki67 and angiogenesis marker CD31. Western-blot analyses of resected tumor lysates revealed a decrease in pAkt and anti-apoptotic protein Bcl2 along with an increase in pAMPK, pro-apoptotic protein Bax and cleaved PARP levels. Importantly, COH-SR4 lead to decrease in the mesenchymal marker vimentin and increase in the normal epithelial marker E-cadherin. The results from our in-vitro and in-vivo studies reveal that COH-SR4 represents a novel candidate with strong mechanistic relevance to target aggressive and drug-resistant lung tumors.

PMID: 24099794 [PubMed - as supplied by publisher]

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STAT3 modulates cigarette smoke-induced inflammation and protease expression.

Front Physiol. 2013;4:267

Authors: Geraghty P, Wyman AE, Garcia-Arcos I, Dabo AJ, Gadhvi S, Foronjy R

Abstract
Signal transducer and activator of transcription-3 (STAT3) regulates inflammation, apoptosis, and protease expression, which are critical processes associated with airway injury and lung tissue destruction. However, the precise role of STAT3 in the development of airway diseases such as chronic obstructive pulmonary disease (COPD) has not been established. This study shows that cigarette smoke activates STAT3 in the lungs of mice. Since cigarette smoke activated STAT3 in the lung, we then evaluated how the loss of STAT3 would impact on smoke-mediated lung inflammation, protease expression, and apoptosis. STAT3(+/+) and STAT3(-/-) mice were exposed to 8 days of cigarette smoke. Compared to the STAT3(+/+) mice bronchoalveolar lavage fluid (BALF) cellularity was significantly elevated in the STAT3(-/-) mice both before and after cigarette smoke exposure, with the increase in cells primarily macrophages. In addition, smoke exposure induced significantly higher BALF protein levels of Interleukin-1α (IL-1α), and monocyte chemotactic protein-1 (MCP-1) and higher tissue expression of keratinocyte chemoattractant (KC) in the STAT3(-/-) mice. Lung mRNA expression of MMP-12 was increased in STAT3(-/-) at baseline. However, the smoke-induced increase in MMP-10 expression seen in the STAT3(+/+) mice was not observed in the STAT3(-/-) mice. Moreover, lung protein levels of the anti-inflammatory proteins SOCS3 and IL-10 were markedly lower in the STAT3(-/-) mice compared to the STAT3(+/+) mice. Lastly, apoptosis, as determined by caspase 3/7 activity assay, was increased in the STAT3(-/-) at baseline to levels comparable to those observed in the smoke-exposed STAT3(+/+) mice. Together, these results indicate that the smoke-mediated induction of lung STAT3 activity may play a critical role in maintaining normal lung homeostasis and function.

PMID: 24101903 [PubMed - as supplied by publisher]

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Advanced bronchoscopic techniques in diagnosis and staging of lung cancer.

J Thorac Dis. 2013 Sep;5(Suppl 4):S359-S370

Authors: Zaric B, Stojsic V, Sarcev T, Stojanovic G, Carapic V, Perin B, Zarogoulidis P, Darwiche K, Tsakiridis K, Karapantzos I, Kesisis G, Kougioumtzi I, Katsikogiannis N, Machairiotis N, Stylianaki A, Foroulis CN, Zarogoulidis K

Abstract
The role of advanced brochoscopic diagnostic techniques in detection and staging of lung cancer has steeply increased in recent years. Bronchoscopic imaging techniques became widely available and easy to use. Technical improvement led to merging in technologies making autofluorescence or narrow band imaging incorporated into one bronchoscope. New tools, such as autofluorescence imagining (AFI), narrow band imaging (NBI) or fuji intelligent chromo endoscopy (FICE), found their place in respiratory endoscopy suites. Development of endobronchial ultrasound (EBUS) improved minimally invasive mediastinal staging and diagnosis of peripheral lung lesions. Linear EBUS proven to be complementary to mediastinoscopy. This technique is now available in almost all high volume centers performing bronchoscopy. Radial EBUS with mini-probes and guiding sheaths provides accurate diagnosis of peripheral pulmonary lesions. Combining EBUS guided procedures with rapid on site cytology (ROSE) increases diagnostic yield even more. Electromagnetic navigation technology (EMN) is also widely used for diagnosis of peripheral lesions. Future development will certainly lead to new improvements in technology and creation of new sophisticated tools for research in respiratory endoscopy. Broncho-microscopy, alveoloscopy, optical coherence tomography are some of the new research techniques emerging for rapid technological development.

PMID: 24102008 [PubMed - as supplied by publisher]

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Adjuvant chemotherapy and radiotherapy in the treatment of non-small cell lung cancer (NSCLC).

J Thorac Dis. 2013 Sep;5(Suppl 4):S371-S377

Authors: Zaric B, Stojsic V, Tepavac A, Sarcev T, Zarogoulidis P, Darwiche K, Tsakiridis K, Karapantzos I, Kesisis G, Kougioumtzi I, Katsikogiannis N, Machairiotis N, Stylianaki A, Foroulis CN, Zarogoulidis K, Perin B

Abstract
Lung cancer is one of the most common human malignancies and remains the leading cause of cancer related deaths worldwide. Many recent technological advances led to improved diagnostics and staging of lung cancer. With development of new treatment options such as targeted therapies there might be improvement in progression free survival of patients with advanced stage non-small cell lung cancer (NSCLC). Improvement in overall survival is still reserved for selected patients and selected treatments. One of the mostly investigated therapeutic options is adjuvant treatment. There are many open issues in selection of patients and administration of appropriate adjuvant treatment.

PMID: 24102009 [PubMed - as supplied by publisher]