• Asian Pacific Journal of Cancer Prevention
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• 제16권4호
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• pp.1507-1513
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• 2015

Pemetrexed is an antifolate agent which has been used for treating malignant pleural mesothelioma and non small lung cancer in the clinic as a chemotherapeutic agent. In this study, pemetrexed inhibited cell growth and induced G1 phase arrest in the A549 cell line. To explore the molecular mechanisms of pemetrexed involved in cell growth, we used a two-dimensional polyacrylamide gel electrophoresis (2-DE) proteomics approach to analyze proteins changed in A549 cells treated with pemetrexed. As a result, twenty differentially expressed proteins were identified by ESI-Q-TOF MS/MS analysis in A549 cells incubated with pemetrexed compared with non-treated A549 cells. Three key proteins (GAPDH, HSPB1 and EIF4E) changed in pemetrexed treated A549 cells were validated by Western blotting. Accumulation of GAPDH and decrease of HSPB1 and EIF4E which induce apoptosis through inhibiting phosphorylation of Akt were noted. Expression of p-Akt in A549 cells treated with pemetrexed was reduced. Thus, pemetrexed induced apoptosis in A549 cells through inhibiting the Akt pathway.

• 대한약학회:학술대회논문집
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• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2-2
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• pp.99.2-99.2
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• 2003

One of the major limitations in using adenoviral vector for gene therapy is inefficient infection of host cells. The presence of coxsackievirus and adenovirus receptor (CAR) and ${\alpha}$-integrin on cell surfaces is required for efficient adenovirus infection. In this study, we investigated the effect of trichostatin A, a histone deacetylase inhibitor, on transfection efficiency after transduction of adenovirus mediated p16$\^$INK4a/ gene transfer. In our previous study, p16$\^$INK4a/ tumor suppressor gene transfer in the non-small cell lung cancer cells (A549 cells) by transduction of recombinant adenovirus (Ad5CMV-p16) resulted in significant inhibition of cancer cell proliferation. (omitted)

• Tuberculosis and Respiratory Diseases
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• 제71권4호
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• pp.259-265
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• 2011

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, are effective therapies for non-small cell lung cancer (NSCLC) patients whose tumors harbor somatic mutations in EGFR. The mutations are, however, only found in about 30% of Asian NSCLC patients and all patients ultimately develop resistance to these agents. Ionizing radiation has been shown to induce autophosphorylation of EGFR and activate its downstream signaling pathways. In the present study, we have tested whether the effect of gefitinib treatment can be enhanced after ionizing radiation. Methods: We compared the PC-9 and A549 cell line with its radiation-resistant derivatives after gefitinib treatment with cell proliferation and apoptosis assay. We also analyzed the effect of gefitinib after ionizing radiation in PC-9, A549, and NCI-H460 cells. Cell proliferation was determined by MTT assay and induction of apoptosis was evaluated by flow cytometry. Caspase 3 activation and PARP cleavage were evaluated by western blot analysis. Results: PC-9 cells having mutated EGFR and their radiation-resistant cells showed no significant difference in cell viability. However, radiation-resistant A549 cells were more sensitive to gefitinib than were their parental cells. This was attributable to an increased induction of apoptosis. Gefitinib-induced apoptosis increased significantly after radiation in cells with wild type EGFR including A549 and NCI-H460, but not in PC-9 cells with mutated EGFR. Caspase 3 activation and PARP cleavage accompanied these findings. Conclusion: The data suggest that gefitinib-induced apoptosis could increase after radiation in cells with wild type EGFR, but not in cells with mutated EGFR.

• Asian Pacific Journal of Cancer Prevention
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• 제14권8호
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• pp.4819-4822
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• 2013

Background: Lung cancer is the leading cause of cancer mortality in the world. Many factors can protect against or facilitate its development. A TNF family member TRAIL, has a complex physiological role beyond that of merely activating the apoptotic pathway in cancer cells. Vitamin D is converted to its active form locally in the lung, and is also thought to play an important role in lung health. Our goal was to investigate the possible clinical significance of serum sTRAIL and 1,25-dihydroxyvitamin D(3) levels in patients with non-small cell lung cancer (NSCLC). Materials and Methods: Totals of 18 consecutive adenocarcinoma and 22 squamous cell carcinoma patients with stage-IV non-small cell lung cancer referred to our institute were included in this study. There were 12 men and 6 women, with ages ranging from 38 to 97 (mean 60.5) years with adenocarcinoma, and 20 men and 2 women, with ages ranging from 46 to 80 (mean 65) years with squamous cell carcinoma. Serum levels of sTRAIL and 1,25-dihydroxyvitamin D(3) were measured in all samples at the time of diagnosis. Results: sTRAIL levels in NSCLC patients were higher than in the control group. Although there was no correlation between patient survival and sTRAIL levels, the highest sTRAIL levels were correlated with age and cigarette smoking in the adenocarcinoma patients. sTRAIL level in healthy individuals were correlated with serum 1,25-dihydroxyvitamin D(3). Conclusions: Serum sTRAIL concentrations were increased in NSCLC patients, and correlated with age and smoking history, but not with overall survival.

• Asian Pacific Journal of Cancer Prevention
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• 제13권5호
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• pp.2355-2362
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• 2012

The SH2B1 adaptor protein is recruited to multiple ligand-activated receptor tyrosine kinases that play important role in the physiologic and pathologic features of many cancers. The purpose of this study was to assess SH2B1 expression and to explore its contribution to the non-small cell lung cancer (NSCLC). Methods: SH2B1 expression in 114 primary NSCLC tissue specimens was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients' outcome. Additionally, 15 paired NSCLC background tissues, 5 NSCLC cell lines and a normal HBE cell line were evaluated for SH2B1 expression by RT-PCR and immunoblotting, immunofluorescence being applied for the cell lines. Results: SH2B1 was found to be overexpressed in NSCLC tissues and NSCLC cell lines. More importantly, high SH2B1 expression was significantly associated with tumor grade, tumor size, clinical stage, lymph node metastasis, and recurrence respectively. Survival analysis demonstrated that patients with high SH2B1 expression had both poorer disease-free survival and overall survival than other patients. Multivariate Cox regression analysis revealed that SH2B1 overexpression was an independent prognostic factor for patients with NSCLC. Conclusions: Our findings suggest that the SH2B1 protein may contribute to the malignant progression of NSCLC and could offer a novel prognostic indicator for patients with NSCLC.

• The Korean Journal of Physiology and Pharmacology
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• 제24권5호
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• pp.413-422
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• 2020

Delphinidin is a major anthocyanidin compound found in various vegetables and fruits. It has anti-oxidant, anti-inflammatory, and various other biological activities. In this study we demonstrated the anti-cancer activity of delphinidin, which was related to autophagy, in radiation-exposed non-small cell lung cancer (NSCLC). Radiosensitising effects were assessed in vitro by treating cells with a subcytotoxic dose of delphinidin (5 μM) before exposure to γ-ionising radiation (IR). We found that treatment with delphinidin or IR induced NSCLC cell death in vitro; however the combination of delphinidin pre-treatment and IR was more effective than either agent alone, yielding a radiation enhancement ratio of 1.54 at the 50% lethal dose. Moreover, combined treatment with delphinidin and IR, enhanced apoptotic cell death, suppressed the mTOR pathway, and activated the JNK/MAPK pathway. Delphinidin inhibited the phosphorylation of PI3K, AKT, and mTOR, and increased the expression of autophagy-induced cell death associated-protein in radiation-exposed NSCLC cells. In addition, JNK phosphorylation was upregulated by delphinidin pre-treatment in radiation-exposed NSCLC cells. Collectively, these results show that delphinidin acts as a radiation-sensitizing agent through autophagy induction and JNK/MAPK pathway activation, thus enhancing apoptotic cell death in NSCLC cells.

• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.965-971
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• 2016

Aims: To investigate the distribution of epidermal growth factor receptor (EGFR) mutations, and explore any relationships with clinical characteristics in non-small-cell lung carcinoma (NSCLC) patients. Materials and Methods: EGFR mutations were assessed by ADx-ARMS in 261 NSCLC patients from West China Hospital of Sichuan University. Relationships between EGFR mutation and clinical characteristics were analyzed by SPSS. Results: The EGFR mutation rate was 48.7% (127/261), 19-del and L858R mutations occurred predominantly, accounting for 33.1% and 40.9%, respectively, in mutated cases. Moreover, 10.2% patients were found to carry double mutations. EGFR mutations occurred more frequently in women (57.5%) than in men (41.8%) (P=0.01), and were more frequent in non-smokers (61.2%) than in former or current smokers (31.2%) (P<0.00). In addition, they were more common in adenocarcinomas (52.8%) and adenosquamous carcinomas (42.8%) than in squamous cell carcinomas (14.8%) (p<0.00). However, only smoking history and pathological types, rather than gender, proved to be associated with EGFR mutations on multivariate logistic regression analysis. No significant differences in pathological stage and metastasis status were found between EGFR wild-type and mutated cases, although EGFR mutation type was related to pathological type (p=0.00) - 19-del, L858R and other mutation types respectively occurred in 34.2%, 42.5% and 23.3% of adenocarcinomas, but in 14.3%, 0% and 85.7% of non-adenocarcinomas. Conclusions: The EGFR mutation rate was 48.7% in NSCLCs in Southwest China, so that nearly 40% patients might benefit from targeted therapies. Smoking status and pathological types were independent predictors of EGFR mutation, while EGFR mutation type was related to only pathological type, rather than smoking status.

• Asian Pacific Journal of Cancer Prevention
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• 제14권4호
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• pp.2563-2566
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• 2013

Background: Interleukin-33 (IL-33) has recently been implicated in tumor immunity. The aim of this study was to explore the clinical role of serum IL-33 in patients with non-small-cell lung cancer (NSCLC). Methods: Sera collected from 250 healthy volunteers (HV), 256 patients with benign lung diseases (BLD) and 262 NSCLC cases were subjected to IL-33 ELISA and relationships between serum IL-33 and clinical characteristics were evaluated. Results: Circulating IL-33 levels were higher in the NSCLC group in comparison with the HV and BLD groups (p<0.001). Using a cut-off level 68 pg/ml (95% specificity in the HV group), IL-33 showed a good diagnostic performance for NSCLC. Multivariate survival analysis indicated that serum IL-33 was an independent prognostic factor in the entire NSCLC group [hazards ratio (HR) = 0.64 for low versus high IL-33 levels, 95% confidence interval (CI) 0.50-0.82; p<0.001] and in 165 selected patients with locally advanced or metastatic disease receiving chemoradiotherapy or chemotherapy (HR 0.70, 95% CI 0.52-0.94; p=0.013). Conclusions: IL-33 is a promising potential diagnostic and prognostic marker in NSCLC, independent of the therapeutic intervention.

• Asian Pacific Journal of Cancer Prevention
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• 제13권9호
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• pp.4739-4743
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• 2012

Background: Predictive biomarkers for lung cancer recurrence after curative tumor resection remain unclear. This study set out to assess the role of FoxM1 in the recurrence of non-small cell lung cancer. Methods: Immunohistochemistry for FoxM1 expression was performed on paraffin-embedded tumor tissues from 165 NSCLC patients. Association of FoxM1 expression with clinicopathological parameters and disease free survival were evaluated. Results: Our results indicated FoxM1 expression to be significantly associated with poorer tissue differentiation (P =0.03), higher TNM stage (P <0.01), lymph node metastasis (P <0.01), advanced tumor stage (P <0.01), and poorer disease free survival (P <0.01). Multivariable analysis showed that FoxM1 expression increased the hazard of recurrence (hazard ratio= 1.96, 95% CI, 1.04-3.17, P <0.05), indicating that FoxM1 is an independent and significant predictor of lung cancer recurrence. Conclusion: Therefore, FoxM1 is an independent risk factor for recurrence of NSCLC. Elevated FoxM1 expression could be used as an indicator of poor disease free survival.

• Asian Pacific Journal of Cancer Prevention
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• 제14권6호
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• pp.3725-3728
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• 2013

Background: The mammalian target of rapamycin (mTOR) /RPS6KB1 activation has recently been implicated in tumour development, but its role in lung cancer remains unclear. The aim of this study was to explore the role of mTOR/RPS6KB1 signaling pathway in non-small-cell lung cancer (NSCLC). Methods: Immunohistochemistry was performed to assess the expression of phosphorylated mammalian target of rapamycin (p-mTOR) and its downstream ribosomal phosphorylated RPS6KB1 (p-RPS6KB1) in NSCLC patients. We also analyzed p-mTOR/p-RPS6KB1 protein expression in 45 fresh NSCLC tissues using Western blotting. Results: The expression level of p-mTOR and p-RPS6KB1 was significantly higher in NSCLC tumor specimens than that in adjacent noncancerous normal lung tissues (P<0.01). p-mTOR expression correlated with p-RPS6KB1. Furthermore, high expression level of p-mTOR or p-RPS6KB1 in NSCLC was associated with a shorter overall survival (both P<0.01). Multivariate analysis indicated high level of p-mTOR expression was an independent prognostic factor (HR=2.642, 95%CI 1.157-4.904, p=0.002). Conclusions: p-mTOR and p-RPS6KB1 could be useful prognostic markers for NSCLC.