The inhibitory effect and mechanism of quetiapine on tumor progression in hepatocellular carcinoma in vivo.

Hepatocellular carcinoma (HCC) is the primary tumor of the liver and the fourth leading cause of cancer-related death. Recently, several studies indicated the anti-tumor potential of antipsychotic medicine. Quetiapine, an atypical antipsychotic, is used to treat schizophrenia, bipolar disorder, and major depressive disorder since 1997. However, whether quetiapine may show potential to suppress HCC progression and its underlying mechanism is persisting unclear. Quetiapine has been shown to induce apoptosis and inhibit invasion ability in HCC in vitro. Here, we established two different HCC (Hep3B, SK-Hep1) bearing animals to identify the treatment efficacy of quetiapine. Tumor growth, signaling transduction, and normal tissue pathology after quetiapine treatment were validated by caliper, bioluminescence image, immunohistochemistry (IHC), and hematoxylin and eosin staining, respectively. Quetiapine suppressed HCC progression in a dose-dependent manner. Extracellular signal-regulated kinases (ERKs) and Nuclear factor-κB (NF-κB) mediated downstream proteins, such as myeloid leukemia cell differentiation protein (MCL-1), cellular FLICE-inhibitory protein (C-FLIP), X-linked inhibitor of apoptosis protein (XIAP), Cyclin-D1, matrix metallopeptidase 9 (MMP-9), vascular endothelial growth factor-A (VEGF-A) and indoleamine 2,3-dioxygenase (IDO) which involved in proliferation, survival, angiogenesis, invasion and anti-tumor immunity were all decreased by quetiapine. In addition, extrinsic/intrinsic caspase-dependent and caspase-independent pathways, including cleaved caspase-3, -8, and - 9 were increased by quetiapine. In sum, the tumor inhibition that results from quetiapine may associate with ERK and NF-κB inactivation.

Fluoxetine Induces Apoptosis through Extrinsic/Intrinsic Pathways and Inhibits ERK/NF-κB-Modulated Anti-Apoptotic and Invasive Potential in Hepatocellular Carcinoma Cells In Vitro.

The aim of the present study was to verify the effects of fluoxetine on dysregulation of apoptosis and invasive potential in human hepatocellular carcinoma (HCC) SK-Hep1 and Hep3B cells. Cells were treated with different concentrations of fluoxetine for different times. MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assays were used for testing the effects of fluoxetine on cell viability. The regulation of apoptosis signaling, and anti-apoptotic, proliferation, and metastasis-associated proteins after fluoxetine treatment were assayed by flow cytometry and Western blotting assay. The detection of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation after fluoxetine treatment was performed by NF-κB reporter gene assay. The results demonstrated that fluoxetine significantly reduced cell viability, cell migration/invasion, NF-κB, extracellular signal-regulated kinases (ERK) activation, and expression of anti-apoptotic (Cellular FLICE (FADD-like IL-1ß-converting enzyme)-inhibitory protein (C-FLIP), Myeloid cell leukemia-1 (MCL-1), X-Linked inhibitor of apoptosis protein (XAIP), and Survivin), proliferation (Cyclin-D1), angiogenesis (vascular endothelial growth factor (VEGF)), and metastasis-associated proteins (matrix metalloproteinase-9 (MMP-9)). Fluoxetine also significantly induced apoptosis, unregulated extrinsic (activation of first apoptosis signal protein and ligand (Fas/FasL), and caspase-8) and intrinsic (loss of mitochondrial membrane potential (ΔΨm) pathways and increased Bcl-2 homologous antagonist killer (BAK) apoptosis signaling. Taken together, these results demonstrated that fluoxetine induced apoptosis through extrinsic/intrinsic pathways and diminished ERK/NF-κB-modulated anti-apoptotic and invasive potential in HCC cells in vitro.

Mammography and the risk of thyroid and hematological cancers: a nationwide population-based study.

To investigate the association between thyroid cancer as well as the most radiosensitive hematological cancers and radiation exposure from mammography. This study used information from a random sample of two million persons enrolled in the nationally representative Taiwan National Health Insurance (NHI) Research Database. The exposed group was composed of women aged 18-65 who had undergone diagnostic mammography between 2000 and 2007. The nonexposed control group was composed of women in the NHI database who had never undergone diagnostic mammography. There were 25,362 women in the exposed group and 203,317 women in the nonexposed group. After adjusting for age and comorbidities, the patients who had been exposed to radiation from mammography did not have a significantly higher risk of developing thyroid cancer and hematological cancers (adjusted HR, 1.201; 95% CI, 0.813-1.774 for thyroid cancer and adjusted HR, 1.228; 95% CI, 0.838-1.800 for hematological cancers). The scattered radiation dose delivered by mammography should be cautiously handled, but no additional concerns about the risk of thyroid cancer developing malignancy should be emphasized.

Hyperforin Suppresses Oncogenic Kinases and Induces Apoptosis in Colorectal Cancer Cells.

BACKGROUND/AIM: Signal transducer and activator of transcription 3 (STAT3), Janus Kinase 1 (JAK1), extracellular signal-regulated kinase (ERK), and protein kinase B (AKT) are essential for malignant transformation and progression in colorectal cancer (CRC) and can be considered as targets for therapeutic interventions. Hyperforin, an active constituent from Hypericum perforatum, has been reported to inhibit inflammation. However, whether hyperforin may suppress CRC progression via inactivation of JAK/STAT3, ERK or AKT signaling remains unclear. MATERIALS AND METHODS: Human CRC cells were used to identify the treatment efficacy of hyperforin and its underlying mechanisms of action by MTT, flow cytometry, wound healing, and western blotting assays. RESULTS: Hyperforin not only induced cytotoxicity, extrinsic/intrinsic apoptosis signaling, but also suppressed the invasion/migration ability of CRC. The phosphorylation of STAT3, JAK1, ERK and AKT was found to be decreased by hyperforin. CONCLUSION: Hyperforin inactivates multiple oncogenic kinases and induces apoptosis signaling in CRC cells.

Imipramine Suppresses Tumor Growth and Induces Apoptosis in Oral Squamous Cell Carcinoma: Targeting Multiple Processes and Signaling Pathways.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) has limited treatment options. This study investigated imipramine, a tricyclic antidepressant, as a potential therapy for OSCC using a SAS-bearing xenograft animal model. MATERIALS AND METHODS: The SAS-bearing xenograft model evaluated imipramine's impact on tumor growth. The control group received no treatment, while the imipramine-treated group received regular doses. Tumor growth, confirmed by imaging, and histological analysis assessed size and weight. Imipramine's effects on apoptosis, epithelial-to-mesenchymal transition (EMT), and transcription factors (AKT, ERK, STAT3) were analyzed. RESULTS: Imipramine significantly suppressed tumor growth within 6 days of treatment, with sustained activity. Computer tomography (CT) scans and histology confirmed reduced size and weight by imipramine. Imipramine induced apoptosis via caspase-dependent/-independent pathways, inhibited EMT, and down-regulated phosphorylated AKT, ERK, and STAT3. CONCLUSION: Imipramine shows promise as an effective OSCC therapy, inhibiting tumor growth, inducing apoptosis, and inhibiting EMT. Its impact on transcription factors and modulation of the AKT/ERK/STAT3 pathway suggest a multifaceted approach.

Reinforcement of Sorafenib Anti-osteosarcoma Effect by Amentoflavone Is Associated With the Induction of Apoptosis and Inactivation of ERK/NF-κB.

BACKGROUND/AIM: Sorafenib has been reported to show anti-osteosarcoma (anti-OS) efficacy by inhibiting metastasis; however, a phase II trial suggested that further combination with other agents could be necessary to achieve permanent remission. Herein, we aimed to identify whether amentoflavone, an abundant natural bioflavonoid found in many medicinal plants, can improve the treatment efficacy of sorafenib in OS. MATERIALS AND METHODS: Cell viability, metastasis, apoptosis, and nuclear translocation of NF-κB after amentoflavone combined with sorafenib were assayed by MTT, transwell migration/invasion, western blotting, flow cytometry, and immunofluorescence staining, respectively. RESULTS: The sorafenib-induced cytotoxicity and apoptosis of U-2 OS was enhanced by combining treatment with QNZ (NF-κB inhibitor) or amentoflavone. NF-κB nuclear translocation, NF-κB phosphorylation, and metastasis capacity of U-2 OS cells were inhibited by amentoflavone combined with sorafenib. CONCLUSION: Amentoflavone may sensitize OS to sorafenib treatment by inducing intrinsic and extrinsic apoptosis and inhibiting ERK/NF-κB signaling transduction.

Magnolol Suppresses ERK/NF-κB Signaling and Triggers Apoptosis Through Extrinsic/Intrinsic Pathways in Osteosarcoma.

BACKGROUND/AIM: Osteosarcoma is an aggressive primary malignant bone tumor that occurs in childhood. Although the diagnostic and treatment options have been improved, osteosarcoma confers poor prognosis. Magnolol, an active component of Magnoliae officinalis cortex, has been widely applied in herb medicine and has been shown to have multiple pharmacological activities. However, whether magnolol possesses anti-osteosarcoma capacity remains unknown. MATERIALS AND METHODS: We examined magnolol is cytotoxicity, and whether it regulates apoptosis and oncogene expression using MTT, flow cytometry and Western blotting assays in osteosarcoma cells. RESULTS: Magnolol exerted toxicity towards U-2 OS cells by inducing intrinsic/extrinsic apoptosis pathways. Additionally, treatment of U-2 OS cells with magnolol inhibited MAPK1 mitogen-activated protein kinase 1 (ERK)/Nuclear factor kappa B (NF-B) signaling involved in tumor progression and reduced the expression of anti-apoptotic and metastasis-associated genes. CONCLUSION: Magnolol may induce apoptosis and inactivate ERK/NF-B signal transduction in osteosarcoma cells.

Beneficial effect of fluoxetine on anti-tumor progression on hepatocellular carcinoma and non-small cell lung cancer bearing animal model.

Fluoxetine, an antidepressant, has been indicated to elicit anti-cancer response in hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) in vitro. However, anticancer effect and mechanism of fluoxetine in HCC and NSCLC in vivo still needs to be elucidated. In this study, we showed anticancer efficacy and inhibitory mechanism of fluoxetine on the tumor progression of HCC and NSCLC in vivo. Tumor growth was significantly inhibited with fluoxetine treatment in HCC and NSCLC in vivo. Fluoxetine obviously decreased expression of cell proliferative, anti-apoptotic, invasion-associated proteins including Cyclin-D1, survivin, vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP-9) and urokinase-type plasminogen activator (uPA). Importantly, fluoxetine diminished the phosphorylation of NF-κB p65 which recognized as one of the critical transcription factors in tumor progression. Inhibition of AKT or extracellular signal-regulated kinases (ERK) phosphorylation was linked to NF-κB inactivation in NSCLC or HCC in vitro. Furthermore, expression of AKT or ERK phosphorylation was effectively attenuated by fluoxetine treatment in NSCLC or HCC in vivo. In addition, fluoxetine also triggered extrinsic/intrinsic apoptotic signaling by activating caspase-3, -8, and -9 in HCC and NSCLC. Our findings suggest that fluoxetine may represent as a promising adjuvant for patients with HCC or NSCLC. In conclude, the results also suggested the blockage of AKT/NF-κB or ERK/NF-κB activation and the induction of apoptosis are associated with fluoxetine-inhibited tumor progression of HCC or NSCLC in vivo.

Well-differentiated epithelial thyroid cancer management in the Asia Pacific region: a report and clinical practice guideline.

CONTEXT: Thyroid cancer is among the 10 most common malignancies in populations in the Asia Pacific region, where access to various relevant health care resources varies widely. OBJECTIVE: An expert consensus conference was held to define regional patterns of practice and guidelines for optimal management of well-differentiated epithelial thyroid carcinomas. RESULTS: Practice patterns vary from country to country, as would be anticipated form their variety of ethnic and racial populations, health care systems, economies, and cultures. Thyroid cancer care is provided by a number of medical and surgical specialists, usually including endocrinologists. The thyroid surgical skills, experience, and outcomes vary widely in the region. Radioiodine is available, to a greater or lesser extent, is almost all countries. Laboratory services for thyroid function monitoring are universally accessible; thyroglobulin assays are available in most countries. Recombinant thyrotropin is approved for use in only two countries, but can be accessed in some others on a "named patient" compassionate need basis. Access to advanced imaging, for exampke, positron emission tomography (PET) scanning, is limited to a few countries. CONCLUSIONS: In light of these realities, appropriate strategies for initial treatment and postoperative monitoring of patients with thyroid cancer have been defined, and these are presented and discussed.

Risk factors in patients with AFB smear-positive sputum who receive inappropriate antituberculous treatment.

BACKGROUND: Acid-fast bacilli (AFB) smear-positive sputum is usually an initial clue in the diagnosis of pulmonary tuberculosis (TB); however, the test is not disease-specific. Nontuberculous mycobacterium-related colonization or lung disease often has AFB smear-positive sputum results, and physicians may prescribe unnecessary antituberculous drugs for these patients. The aim of this study was to analyze the clinical characteristics of patients with AFB smear-positive sputum who received unnecessary anti-TB treatment. METHODS AND PATIENTS: From January 2008 to July 2011, we retrospectively enrolled 97 patients with AFB smear-positive sputum who did not have pulmonary TB according to mycobacterial cultures and clinical judgment. We analyzed the clinical and radiographic features of the patients who received inappropriate and unnecessary anti-TB treatment. Preliminary analyses of chisquare and Fisher's exact tests were applied to determine factors unlikely to be associated with the independent variables. The relationship between independent covariates was then analyzed using multivariate logistic regression. RESULTS: Of the 97 enrolled patients, 25 (25.8%) were diagnosed with pulmonary TB and prescribed anti-TB drugs (mostly a combination of isoniazid, rifampicin, ethambutol, and pyrazinamide). The other 72 (74.2%) patients were not initially diagnosed with pulmonary TB and were classified as the control group. Compared to the control group, the patients who received inappropriate anti-TB treatment had more chronic cough as presentation symptom and heavy AFB Ziehl-Neelsen staining in sputum (>10/100 fields, grading 2+ to 4+). There were no significant differences in the radiographic analysis between the two groups. CONCLUSION: Among the patients with AFB smear-positive sputum that did not have pulmonary TB, chronic cough and heavy AFB staining (2+ to 4+) were risk factors for the inappropriate administration of unnecessary anti-TB treatment.

Bacterial pneumonia following acute ischemic stroke.

BACKGROUND: The most common serious complication following acute ischemic stroke is pneumonia, which may increase mortality and worsen clinical outcomes. The purpose of this study was to investigate the predictors of 30-day mortality in patients with pneumonia following acute ischemic stroke. METHODS: From June 2006 to May 2011, we retrospectively included 51 patients with pneumonia following acute ischemic stroke. We analyzed the clinical features, microbiologic data, and outcomes. Predictors of 30-day mortality were investigated by univariate and multivariate analysis. RESULTS: The acute ischemic strokes were caused by large-artery atherosclerosis in 37 (72.5%) of the 51 patients. We found that the most common pathogen responsible for poststroke pneumonia was Klebsiella pneumoniae, followed by Pseudomonas aeruginosa and Escherichia coli. Ultimately, 12 patients died of progressive sepsis due to pneumonia after the acute ischemic stroke. The 30-day mortality rate was 23.5%. In the univariate analysis, patients who died within 30 days had higher National Institutes of Health Stroke Scale scores, higher CURB-65 scores, elevated instability of hemodynamic status, and lower Glasgow Coma Scale (GCS) scores. In Cox regression analysis, a GCS score of <9 on the day of pneumonia onset was only significant indicator for 30-day mortality (hazard ratio, 6.72; 95% confidence interval, 2.12-21.30, p = 0.001). CONCLUSION: Pneumonia after acute ischemic stroke is a severe complication. Once stroke-related pneumonia develops, neurologic assessment, CURB-65 score, and shock can be used to predict the ultimate prognosis.