Potential Antitumor Activity of SIM-89 in Non-Small Cell Lung Cancer Cells

PURPOSE: c-Met and its ligand, hepatocyte growth factor (HGF), play a critical role in oncogenesis and metastatic progression. The aim of this study was to identify inhibited enzymogram and to test the antitumor activity of SIM-89 (a c-Met receptor tyrosine kinase inhibitor) in non-small cell lung cancer. MATERIALS AND METHODS: Z′-LYTE kinase assay was employed to screen the kinase enzymogram, and mechanism of action (MOA) analysis was used to identify the inhibited kinases. Cell proliferation was then analyzed by CCK8 assay, and cell migration was determined by transwell assay. The gene expression and the phosphorylation of c-Met were examined by realtime-PCR and western blotting, respectively. Finally, the secretion of HGF was detected by ELISA assay. RESULTS: c-Met, activated protein kinase (AMPK), and tyrosine kinase A (TRKA) were inhibited by SIM-89 with the IC₅₀ values of 297 nmol/L, 1.31 µmol/L, and 150.2 nmol/L, respectively. SIM-89 exerted adenosine triphosphate (ATP) competitive inhibition on c-Met. Moreover, the expressions of STAT1, JAK1, and c-Met in H460 cells were decreased by SIM-89 treatment, and c-Met phosphorylation was suppressed in A549, H441, H1299, and B16F10 cells by the treatment. In addition, SIM-89 treatment significantly decreased the level of HGF, which accounted for the activation of c-Met receptor tyrosine kinase. Finally, we showed cell proliferation inhibition and cell migration suppression in H460 and H1299 cells after SIM-89 treatment. CONCLUSION: In conclusion, SIM-89 inhibits tumor cell proliferation, migration and HGF autocrine, suggesting it's potential antitumor activity.

Anti-tumor activities of CIK cells derived from lymph nodes of lung cancer patients / 中国癌症杂志

Background and purpose:Cytokine-induced killer (CIK) has both the advantages of T lympho-cytes’ powerful anti-tumor activity and NK cells’ tumor killing capacity without MHC restriction. It could directly kill tumor cells, regulate and enhance immune function, without damaging the structure and functions of the immune sys-tem. Its effects on the treatment of malignant solid tumors has been widely recognized. This study aimed to evaluate the anti-proliferation effects of CIK cells obtained and cultivated from lung cancer patients’ lymph nodes. Meanwhile, the safety of clinical transfusion was observed.Methods:The peripheral blood and lymph nodes of 6 surgery patients with lung cancer from Shanghai Chest Hospital were used to cultivate CIK cells for 14 days. The phenotypes of CIK cells were detected by lfow cytometry. The anti-proliferation activities of CIK cells on A549 lung cancer cells were detected by CCK8 assay. The morphological changes of CIK cells were observed by invert microscope. The expression of CEA level and adverse events were evaluated after CIK transfusion.Results:The proportion of CD3+CD56+T lymphocyte in two groups were both more than 30%. The CCK8 assay showed that the suppression rate of lymph nodes group was higher than that of peripheral blood group at each effect/target ratio(P<0.05). The adverse effect of CIK transfusion was mild and tolerable. The expression of CEA level decreased in patients.Conclusion:Lymph nodes of surgery patients with lung cancer can be used for cultivation of CIK cells. The anti-tumor activity of CIK isolated from lymph nodes is better than that of CIK cells cultivated from peripheral blood. Preclinical experiments showed high safety.

The value of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of intrathoracic tuberculosis / 中华胸心血管外科杂志

Objective To evaluate the diagnostic value of endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA) in intrathoracic tuberculosis(TB).Methods We retrospectively analyzed patients underwent EBUS-TBNA with a final diagnosis of intrathoracic TB at Shanghai Chest Hospital from October 2009 to March 2013 and observed that the diagnostic efficacy by pathology and microbiology and safety of EBUS-TBNA for intrathoracic TB.Results 75 patients were diagnosed with pulmonary TB or intrathoracic tuberculous lymphadenitis,and accuracy was 80％ (60/75) by EBUS TBNA.A total of 60 patients had pathology,acid-fast bacilli(AFB) staining and mycobacterial culture test results,of whom 52 (86.67％)were diagnosed.Pathological findings were consistent with TB in 77.33％ patients (58/75),in 20.31％ (13/64) the smear were positive for AFB and in 46.67％ (28/60) were positive for cuhure.One hundred and twenty-nine mediastinal or hilar lymph nodes and 10 intrapulmonary lesions were biopsied in 75 patients,the average target number of per patient were 1.85.Pathological findings were consistent with TB in 66.19％ samples(92/139),in 13.91％ (16/115) were positive for AFB and in 38.32％ (41/107) were positive for culture.Multivariate regression revealed that short-axis diameter was an independent risk factor associated with positive pathology,smear and euhure.Additionally,more aspiration times cause higher pathology positive rate,pathology showing necrosis and positive smear were independent risk factors associated with positive cuhure.There were two patients occurred complications during operation.Conclusion EBUS-TBNA was a safe and effective method for the diagnosis of intrathoracic tuberculosis.

Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of non-lymph node thoracic lesions

Endobronchial ultrasound-guided transbronchial needle aspiration [EBUS-TBNA] has shown excellent diagnostic capabilities for mediastinal and hilar lymphadenopathy. However, its value in thoracic non-lymph node lesions is less clear. This study was designed to assess the value of EBUS-TBNA in distinguishing malignant from benign thoracic non-lymph node lesions. From October 2009 to August 2011, 552 patients underwent EBUS-TBNA under local anesthesia and with conscious sedation. We retrospectively reviewed 81 of these patients who had tracheobronchial wall-adjacent intrapulmonary or isolated mediastinal non-lymph node lesions. On-site cytological evaluation was not used. Immunohistochemistry [IHC] was performed to distinguish the origin or type of malignancy when necessary. EBUS-TBNA was performed in 68 tracheobronchial wall-adjacent intrapulmonary and 13 isolated mediastinal non-lymph node lesions. Of the 81 patients, 77 [95.1%, 60 malignancies and 17 benignancies] were diagnosed through EBUS-TBNA, including 57 primary lung cancers, 2 mediastinal tumors, 1 pulmonary metastatic adenocarcinoma, 7 inflammation, 5 tuberculosis, 3 mediastinal cysts, 1 esophageal schwannoma, and 1 focal fibrosis. There were four false-negative cases [4.9%]. Of the 60 malignancies, there were 9 [15.0%] which originally had no definite histologic origin or type. Thus, IHC was performed, with 7 [77.8%] being subsequently confirmed. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in distinguishing malignant from benign lesions were 93.4% [60/64], 100% [17/17], 100% [60/60], 81.0% [17/21], and 95.1% [77/81], respectively. EBUS-TBNA is a safe procedure with a high sensitivity for distinguishing malignant from benign thoracic non-lymph node lesions within the reach of EBUS-TBNA, with IHC usually providing a more definitive diagnosis