Ki-Eun Hwang

Effect of simvastatin on the resistance to EGFR tyrosine kinase inhibitors in a non-small cell lung cancer with the T790M mutation of EGFR.

Although non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are highly responsive to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib, development of acquired resistance is almost inevitable. Statins show antitumor activity, but it is unknown whether they can reverse EGFR-TKIs resistance in NSCLC with the T790M mutation of EGFR. This study investigated overcoming resistance to EGFR-TKI using simvastatin. We demonstrated that addition of simvastatin to gefitinib enhanced caspase-dependent apoptosis in T790M mutant NSCLC cells. Simvastatin also strongly inhibited AKT activation, leading to suppression of β-catenin activity and the expression of its targets, survivin and cyclin D1. Both insulin treatment and AKT overexpression markedly increased p-β-catenin and survivin levels, even in the presence of gefitinib and simvastatin. However, inhibition of AKT by siRNA or LY294002 treatment decreased p-β-catenin and survivin levels. To determine the role of survivin in simvastatin-induced apoptosis of gefitinib-resistant NSCLC, we showed that the proportion of apoptotic cells following treatment with survivin siRNA and the gefitinib-simvastatin combination was greater than the theoretical additive effects, whereas survivin up-regulation could confer protection against gefitinib and simvastatin-induced apoptosis. Similar results were obtained in erlotinib and simvastatin-treated HCC827/ER cells. These findings suggest that survivin is a key molecule that renders T790M mutant NSCLC cells resistant to apoptosis induced by EGFR-TKIs and simvastatin. Overall, these data indicate that simvastatin may overcome EGFR-TKI resistance in T790M mutant NSCLCs via an AKT/β-catenin signaling-dependent down-regulation of survivin and apoptosis induction.

Case of Pseudomembranous Necrotizing Tracheobronchial Aspergillosis in an Immunocompetent Host

A 44-year-old Korean male died of rapidly progressive respiratory failure and refractory hypoxemia in 8 days after being admitted with a fever and dyspnea. The patient was diagnosed with pseudomembranous necrotizing tracheobronchial aspergillosis by fibroptic bronchoscopy and it was not related to an invasion of the pulmonary parenchyma. To the best of our knowledge, this case represents a patient with pseudomembranous necrotizing tracheobronchial aspergillosis that developed in an immunocompetent host, rapidly resulting in airway obstruction with acute respiratory failure and refractory hypoxemia without an invasion of the pulmonary parenchyma.

SRSF5: a novel marker for small-cell lung cancer and pleural metastatic cancer.

OBJECTIVES SR-splicing factors (SRSFs) play important roles in oncogenesis. However, the expression of SRSF 5-7 proteins in lung cancer (LC) is unclear, and their use in the diagnosis of pleural diseases has never been assessed. We evaluated SRSF 5-7 protein levels in LC and their diagnostic potential for cancer cells in lung and pleural effusion (PE) and, for the dysregulated SRSFs, investigated their neutralization effect on LC. MATERIALS AND METHODS SRSF 5-7 levels in lung tissue and PE cell lysate samples (n=453) were compared with the results of conventional tumor markers. Knockdown of SRSF gene expression was performed using small interfering RNAs on small-cell LC (SCLC) cell lines. RESULTS In lung tissue analysis, SRSF 5-7 levels were up-regulated in LC samples compared with non-tumoral lung tissue samples; they were markedly higher in SCLC than in adenocarcinoma or squamous cell carcinoma. SRSF5 showed the highest detection accuracy (89%) for total LC, and it was superior to that (74%) of carcinoembryonic antigen [CEA, a commonly used non-SCLC (NSCLC) marker]. Notably, the detection accuracies of the three SRSFs for SCLC were all 100% and higher than that (69%) of a pro-gastrin-releasing peptide (a well-known SCLC marker). In PE cell analysis, the detection accuracy (86%) of SRSF5 for malignant cells was highest among SRSFs and comparable to that (83%) of CEA. SRSF5 additionally detected 70% of CEA-missed non-NSCLC cases. Down-regulation of the SRSFs induced mild (SRSF5 and SRSF7) to remarkably (SRSF6) reduced cell proliferation. CONCLUSIONS Our results demonstrated the up-regulated expression of SRSF 5-7 proteins in LC with much more profound up-regulation in SCLC than in NSCLC and suggest that up-regulation of the SRSFs is related to SCLC proliferation. Moreover, we identified SRSF5 as a novel detection marker for SCLC and pleural metastatic cancer cells.

Transformation to small cell lung cancer as an acquired resistance mechanism in EGFR-mutant lung adenocarcinoma: a case report of complete response to etoposide and cisplatin.

First-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for patients with advanced non-small cell lung cancer who were selected on the basis of EGFR mutations have improved the progression-free survival with acceptable toxicity compared to standard chemotherapy. However, acquired resistance to EGFR-TKIs has been identified as an important clinical problem. Transformation to small cell lung cancer (SCLC) is a rare mechanism of resistance to EGFR-TKI therapy. We describe the case of a 61-year-old man who presented transformation from adenocarcinoma to SCLC as the manifestation of acquired resistance after EGFR-TKI treatment. He underwent chemotherapy with etoposide and cisplatin and achieved a complete response.

Pseudoaneurysm due to squamous cell carcinoma of the lung: two cases of spontaneous resolution after chemotherapy.

Pseudoaneurysm due to cancer is uncommon generally and is extremely rare in lung cancer. We report two cases of false aneurysms due to lung cancer that spontaneously regressed upon chemotherapy without intervention. Both patients had squamous cell carcinoma of the lung and the diagnosis of a pseudoaneurysm was made using computed tomography. There was no evidence of severe bronchial hemorrhage and the pseudoaneurysms were small and well-encased. Chemotherapy was performed and the pseudoaneurysms resolved.

The prognosis of patients with lung cancer admitted to the medical intensive care unit

Lung cancer remains the leading cause of cancer mortality worldwide. Despite their poor prognosis, patients with lung cancer are increasingly being admitted to the medical intensive care unit (MICU) for treatment of critical illnesses. The aim of this study was to assess the outcome of patients with lung cancer who are admitted to an MICU and to identify the measurable predictors of their MICU outcome.

Celecoxib and sulindac inhibit TGF-β1-induced epithelial-mesenchymal transition and suppress lung cancer migration and invasion via downregulation of sirtuin 1

The non-steroidal anti-inflammatory drugs (NSAIDs) celecoxib and sulindac have been reported to suppress lung cancer migration and invasion. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. However, its role in inhibition of lung cancer cell epithelial-mesenchymal transition (EMT) by NSAIDs is not clearly known. We attempted to investigate the potential use of NSAIDs as inhibitors of TGF-β1-induced EMT in A549 cells, and the underlying mechanisms of suppression of lung cancer migration and invasion by celecoxib and sulindac. We demonstrated that celecoxib and sulindac were effective in preventing TGF-β1-induced EMT, as indicated by upregulation of the epithelial marker, E-cadherin, and downregulation of mesenchymal markers and transcription factors. Moreover, celecoxib and sulindac could inhibit TGF-β1-enhanced migration and invasion of A549 cells. SIRT1 downregulation enhanced the reversal of TGF-β1-induced EMT by celecoxib or sulindac. In contrast, SIRT1 upregulation promoted TGF-β1-induced EMT. Taken together, these results indicate that celecoxib and sulindac can inhibit TGF-β1-induced EMT and suppress lung cancer cell migration and invasion via downregulation of SIRT1. Our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse TGF-β1-induced EMT and to prevent lung cancer cell migration and invasion.

Pleural fluid characteristics of pleuropulmonary paragonimiasis masquerading as pleural tuberculosis

Background/Aims Pleuropulmonary paragonimiasis produces no specific symptoms or radiologic findings, allowing for the possibility of misdiagnosis. We evaluated the specific clinical and pleural fluid features of pleuropulmonary paragonimiasis masquerading as pleural tuberculosis. Methods We retrospectively analyzed the clinical and radiologic characteristics of 20 patients diagnosed with pleuropulmonary paragonimiasis between 2001 and 2011. Results In total, 17 patients presented with respiratory symptoms, including dyspnea (30%), hemoptysis (20%), cough (20%), and pleuritic chest pain (15%). Chest radiographs revealed intrapulmonary parenchymal lesions, including air-space consolidation (30%), nodular opacities (20%), cystic lesions (15%), ground-glass opacities (10%), and pneumothorax (5%). A pleural f luid examination revealed eosinophilia, low glucose levels, and high lactate dehydrogenase (LDH) levels in 87%, 76%, and 88% of the patients, respectively. These traits helped to distinguish pleuropulmonary paragonimiasis from other pleural diseases such as parapneumonic effusion, malignancy, and pleural tuberculosis. Conclusions Pleuropulmonary paragonimiasis is often initially misdiagnosed as other pleural diseases. Therefore, it is important to establish the correct diagnosis. In patients with unexplained pleural effusion living in paragonimiasis-endemic areas, pleural fluid obtained by thoracentesis should be examined to distinguish pleuropulmonary paragonimiasis. When marked eosinophilia, high LDH levels, and low glucose levels are identified in pleural fluid, physicians could consider a diagnosis of pleuropulmonary paragonimiasis.

Shikonin-induced necroptosis is enhanced by the inhibition of autophagy in non-small cell lung cancer cells

BackgroundShikonin, a natural naphthoquinone pigment purified from Lithospermum erythrorhizon, induces necroptosis in various cancer types, but the mechanisms underlying the anticancer activity of shikonin in lung cancer are not fully understood. This study was designed to clarify whether shikonin causes necroptosis in non-small cell lung cancer (NSCLC) cells and to investigate the mechanism of action.MethodsMultiplex and caspase 8 assays were used to analyze effect of shikonin on A549 cells. Cytometry with annexin V/PI staining and MTT assays were used to analyze the mode of cell death. Western blotting was used to determine the effect of shikonin-induced necroptosis and autophagy. Xenograft and orthotopic models with A549 cells were used to evaluate the anti-tumor effect of shikonin in vivo.ResultsMost of the cell death induced by shikonin could be rescued by the specific necroptosis inhibitor necrostatin-1, but not by the general caspase inhibitor Z-VAD-FMK. Tumor growth was significantly lower in animals treated with shikonin than in the control group. Shikonin also increased RIP1 protein expression in tumor tissues. Autophagy inhibitors, including methyladenine (3-MA), ATG5 siRNA, and bafilomycin A, enhanced shikonin-induced necroptosis, whereas RIP1 siRNA had no effect on the apoptotic potential of shikonin.ConclusionsOur data indicated that shikonin treatment induced necroptosis and autophagy in NSCLC cells. In addition, the inhibition of shikonin-induced autophagy enhanced necroptosis, suggesting that shikonin could be a novel therapeutic strategy against NSCLC.

Synergistic Effect of Sulindac and Simvastatin on Apoptosis in Lung Cancer A549 Cells through AKT-Dependent Downregulation of Survivin

Purpose Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive or chemotherapeutic agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in human non-small cell lung cancer cells has not been elucidated. In this study, we investigated the synergistic interaction of sulindac and simvastatin in lung cancer A549 cells. Materials and Methods Cell viability was measured by an MTT assay, while the expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by Western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. Reactive oxygen species (ROS) generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac- and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin. Results Sulindac and simvastatin synergistically augmented apoptotic activity and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, while AKT overexpression markedly increased survivin expression, even in the presence of sulindac and simvastatin. Moreover, survivin siRNA enhanced sulindac- and simvastatininduced apoptosis. In contrast, survivin upregulation protected against sulindac- and simvastatin-induced apoptosis. Conclusion Combined treatment with sulindac and simvastatin augmented their apoptotic potential in lung cancer cells through AKT signaling-dependent downregulation of survivin. These results indicate that sulindac and simvastatin may be clinically promising therapies for the prevention of lung cancer.