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Lin H.-P.,National Health Research Institute | Lin C.-Y.,National Health Research Institute | Huo C.,National Health Research Institute | Huo C.,National Central University | And 14 more authors.
Oncotarget | Year: 2015

Prostate cancer (PCa) patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant prostate cancer (CRPC) within 1-3 years. Treatment with caffeic acid phenethyl ester (CAPE) suppressed cell survival and proliferation via induction of G1 or G2/M cell cycle arrest in LNCaP 104-R1, DU-145, 22Rv1, and C4-2 CRPC cells. CAPE treatment also inhibited soft agar colony formation and retarded nude mice xenograft growth of LNCaP 104-R1 cells. We identified that CAPE treatment significantly reduced protein abundance of Skp2, Cdk2, Cdk4, Cdk7, Rb, phospho-Rb S807/811, cyclin A, cyclin D1, cyclin H, E2F1, c-Myc, SGK, phospho-p70S6kinase T421/S424, phospho-mTOR Ser2481, phospho-GSK3a Ser21, but induced p21Cip1, p27Kip1, ATF4, cyclin E, p53, TRIB3, phospho-p53 (Ser6, Ser33, Ser46, Ser392), phospho-p38 MAPK Thr180/Tyr182, Chk1, Chk2, phospho-ATM S1981, phospho-ATR S428, and phospho-p90RSK Ser380. CAPE treatment decreased Skp2 and Akt1 protein expression in LNCaP 104-R1 tumors as compared to control group. Overexpression of Skp2, or siRNA knockdown of p21Cip1, p27Kip1, or p53 blocked suppressive effect of CAPE treatment. Co-treatment of CAPE with PI3K inhibitor LY294002 or Bcl-2 inhibitor ABT737 showed synergistic suppressive effects. Our finding suggested that CAPE treatment induced cell cycle arrest and growth inhibition in CRPC cells via regulation of Skp2, p53, p21Cip1, and p27Kip1.


Lee T.-M.,China Medical University An Nan Hospital | Lee T.-M.,China Medical University at Taichung | Lee T.-M.,Taipei Medical University | Lin S.-Z.,China Medical University at Taichung | And 4 more authors.
Free Radical Biology and Medicine | Year: 2014

Glycogen synthase kinase-3 (GSK-3) signaling has been shown to play a role in the regulation of nuclear factor erythroid-2-related factor 2 (Nrf2), a master regulator of antioxidant genes, including heme oxygenase-1 (HO-1). We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction, a status of high reactive oxygen species (ROS), by attenuating nerve growth factor (NGF) expression and whether Nrf2/HO-1 signaling is involved in the protection. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats were treated for 4 weeks. The postinfarction period was associated with increased oxidative-nitrosative stress, as measured by myocardial superoxide, nitrotyrosine, and dihydroethidium fluorescent staining. In concert, myocardial norepinephrine levels and immunohistochemical analysis of sympathetic nerve revealed a significant increase in innervation in vehicle-treated rats compared with sham-operated rats. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those in sham. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administration of LiCl. LiCl stimulated the nuclear translocation of Nrf2 and the transactivation of the Nrf2 target gene HO-1. Inhibition of phosphoinositide 3-kinase by wortmannin reduced the increase in Nrf2 nucleus translocation and HO-1 expression compared with lithium alone. In addition, the lithium-attenuated NGF levels were reversed in the presence of the Nrf2 inhibitor trigonelline, HO-1 inhibitor SnPP, and peroxynitrite generator SIN-1, indicating the role of Nrf2/HO-1/ROS. In conclusion, lithium protects against ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via antioxidant activation of the Nrf2/HO-1 axis. © 2014 Elsevier B.V. All rights reserved.


Lee T.-M.,China Medical University An Nan Hospital | Lee T.-M.,China Medical University at Taichung | Lee T.-M.,Taipei Medical University | Lin S.-Z.,China Medical University at Taichung | And 4 more authors.
Journal of Cellular and Molecular Medicine | Year: 2014

Clinical and experimental studies have established that gender is a factor in the development of ventricular hypertrophy. We investigated whether the attenuated hypertrophic effect of oestradiol was via activation of phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) through non-genomic action. Twenty-four hours after coronary ligation, female Wistar rats were randomized into control, subcutaneous oestradiol treatment or a G-protein coupled oestrogen receptor (GPER) agonist, G-1 and treated for 4 weeks starting from 2 weeks after bilateral ovariectomy. Ventricular hypertrophy assessed by cardiomyocyte size after infarction was similarly attenuated by oestradiol or G-1 in infarcted rats. The phosphorylation of Akt and eNOS was significantly decreased in infarcted rats and restored by oestradiol and G-1, implying the GPER pathway in this process. Oestradiol-induced Akt phosphorylation was not abrogated by G-15 (a GPER blocker). Akt activation was not inhibited by actinomycin D. When a membrane-impermeable oestrogen-albumin construct was applied, similar responses in terms of eNOS activation to those of oestradiol were achieved. Furthermore, PPT, an ERα receptor agonist, activated the phosphorylation of Akt and eNOS. Thus, membrane ERα receptor played a role in mediating the phosphorylation of Akt and eNOS. The specific PI3K inhibitor, LY290042, completely abolished Akt activation and eNOS phosphorylation in infarcted hearts treated with either oestradiol or oestradiol + G-15. These data support the conclusions that oestradiol improves ventricular remodelling by both GPER- and membrane-bound ERα-dependent mechanisms that converge into the PI3K/Akt/eNOS pathway, unveiling a novel mechanism by which oestradiol regulates pathological cardiomyocyte growth after infarction. © 2014 The Authors.


PubMed | China Medical University at Taichung, Taipei Medical University Hospital and China Medical University An Nan Hospital
Type: Journal Article | Journal: Bioscience reports | Year: 2016

Myocardial infarction (MI) was associated with insulin resistance, in which resistin acts as a critical mediator. We aimed to determine whether sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, can attenuate arrhythmias by regulating resistin-dependent nerve growth factor (NGF) expression in postinfarcted rats. Normoglycaemic male Wistar rats after ligating coronary artery were randomized to either vehicle or sitagliptin for 4weeks starting 24h after operation. Post-infarction was associated with increased myocardial noradrenaline [norepinephrine (NE)] levels and sympathetic hyperinnervation. Compared with vehicle, sympathetic innervation was blunted after administering sitagliptin, as assessed by immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and western blotting and real-time quantitative RT-PCR of NGF. Arrhythmic scores in the sitagliptin-treated infarcted rats were significantly lower than those in vehicle. Furthermore, sitagliptin was associated with reduced resistin expression and increased Akt activity. Ex vivo studies showed that glucose-dependent insulinotropic polypeptide (GIP) infusion, but not glucagon-like peptide-1 (GLP-1), produced similar reduction in resistin levels to sitagliptin in postinfarcted rats. Furthermore, the attenuated effects of sitagliptin on NGF levels can be reversed by wortmannin (a phosphatidylinositol 3-kinase antagonist) and exogenous resistin infusion. Sitagliptin protects ventricular arrhythmias by attenuating sympathetic innervation in the non-diabetic infarcted rats. Sitagliptin attenuated resistin expression via the GIP-dependent pathway, which inhibited sympathetic innervation through a signalling pathway involving phosphatidylinositol 3-kinase (PI3K) and Akt protein.


Chiu H.-W.,National Cheng Kung University | Chiu H.-W.,Taipei Medical University | Tseng Y.-C.,National Cheng Kung University | Hsu Y.-H.,Taipei Medical University | And 8 more authors.
Cancer Letters | Year: 2015

Sarcoma is a rare form of cancer that differs from the much more common carcinomas because it occurs in a distinct type of tissue. Many patients of sarcoma have poor response to chemotherapy and an increased risk for local recurrence. Arsenic trioxide (ATO) is used to treat certain types of leukemia. Recently, data have revealed that ATO induces sarcoma cell death in several types of solid tumor cell lines. In the present study, we investigated whether ATO induces cancer cell death and elucidated the underlying anti-cancer mechanisms. Our results showed that ATO caused concentration- and time-dependent cell death in human osteosarcoma and fibrosarcoma cells. The types of cell death that were induced by ATO were primarily autophagy and apoptosis. Furthermore, ATO activated p38, JNK and AMPK and inhibited the Akt/mTOR signaling pathways. Specifically, we found that ATO induced endoplasmic reticulum (ER) stress and suppressed proteasome activation in two types of sarcoma cell lines. However, the level of proteasome inhibition in osteosarcoma cells was lower than in fibrosarcoma cells. Thus, we used combined treatment with ATO and a proteasome inhibitor to examine the antitumor activity in fibrosarcoma cells. The data indicated showed that the combination treatment of ATO and MG132 (a proteasome inhibitor) resulted in synergistic cytotoxicity. In a fibrosarcoma xenograft mouse model, the combined treatment significantly reduced tumor progression. Immunohistochemical studies revealed that combined treatment induced autophagy and apoptosis. In summary, our results suggest a potential clinical application of ATO in sarcoma therapy and that combined treatment with a proteasome inhibitor can increase the therapeutic efficacy. © 2014 Elsevier Ireland Ltd.


Leung H.W.C.,China Medical University An Nan Hospital | Chan A.L.F.,China Medical University An Nan Hospital | Muo C.-H.,Data Management
Journal of Cardiology | Year: 2016

Purpose: The purpose of this study was to assess the long-term cardiac morbidity and mortality after breast irradiation using contemporary irradiation techniques. Methods: We used the Catastrophic Illness dataset from the National Health Insurance Research Database to explore the possible association between late cardiotoxicity and women with early breast cancer treated with breast conservation therapy from 2000 to 2010. The Cox proportional-hazards model was used to compare breast cancer patients who received adjuvant radiotherapy versus without adjuvant radiotherapy for the end points with the following primary diagnoses (International Classification of Diseases, 9th Revision codes): ischemic heart disease (410-414, 36.0, 36.1), valvular heart disease (394-397, 424, 35), congestive heart failure (428, 402.01, 402.11, 402.91), and conduction abnormalities (426, 37.7-37.8, 37.94-37.99). Results: Three hundred and thirty patients received adjuvant radiotherapy and 4802 patients did not receive radiotherapy. Median follow-up was 3.5 years. There was no difference in overall morbidity and mortality from any cardiac cause (p = 0.13) in breast cancer patients who received adjuvant radiotherapy versus without radiotherapy by using modern radiotherapy techniques. Conclusion: There were no significant differences in cardiac morbidity and mortality after radiotherapy for breast cancer with a 9-year follow-up period in our population. © 2015 Japanese College of Cardiology.


PubMed | China Medical University An Nan Hospital and Data Management
Type: Journal Article | Journal: Journal of cardiology | Year: 2016

The purpose of this study was to assess the long-term cardiac morbidity and mortality after breast irradiation using contemporary irradiation techniques.We used the Catastrophic Illness dataset from the National Health Insurance Research Database to explore the possible association between late cardiotoxicity and women with early breast cancer treated with breast conservation therapy from 2000 to 2010. The Cox proportional-hazards model was used to compare breast cancer patients who received adjuvant radiotherapy versus without adjuvant radiotherapy for the end points with the following primary diagnoses (International Classification of Diseases, 9th Revision codes): ischemic heart disease (410-414, 36.0, 36.1), valvular heart disease (394-397, 424, 35), congestive heart failure (428, 402.01, 402.11, 402.91), and conduction abnormalities (426, 37.7-37.8, 37.94-37.99).Three hundred and thirty patients received adjuvant radiotherapy and 4802 patients did not receive radiotherapy. Median follow-up was 3.5 years. There was no difference in overall morbidity and mortality from any cardiac cause (p=0.13) in breast cancer patients who received adjuvant radiotherapy versus without radiotherapy by using modern radiotherapy techniques.There were no significant differences in cardiac morbidity and mortality after radiotherapy for breast cancer with a 9-year follow-up period in our population.


PubMed | Tzu Chi University, Taipei Medical University and China Medical University An Nan Hospital
Type: | Journal: Laboratory investigation; a journal of technical methods and pathology | Year: 2016

Although endothelin (ET)-1 has been shown to upregulate nerve growth factor (NGF) expression, the molecular mechanisms are largely unknown. Phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase (GSK)-3 signal has been implicated in the regulation of NGF. We investigated whether selective ET receptor blockers attenuated cardiac sympathetic reinnervation through restoring PI3K/Akt/GSK-3 activity. After ligation of the left anterior descending artery, male Wistar rats were randomized to either vehicle, atrasentan (an ET


Leung H.W.C.,China Medical University An Nan Hospital | Chan A.L.F.,China Medical University An Nan Hospital
Expert Opinion on Drug Safety | Year: 2015

Background: We conducted a meta-analysis to assess the overall risk of cardiac toxicity associated with trastuzumab treatment in elderly breast cancer patients. Methods: We searched databases from PubMed, EMBASE and Cochrane Central Registry of Controlled Trials to identify relevant studies. Statistical analyses were conducted to calculate the incidence rate, overall hazard ratio (HR) and 95% CIs using a fixed effects model. Results: A total of 116,342 and 360 elderly patients from five cohort studies and two randomized clinical trials (RCTs) were included for analysis. The pooled incidences of symptomatic congestive heart failure (CHF) and CHF/HF/CM were 6.4% (95% CI 4.1% - 9.4) and 16.4% (95% CI 16.19% - 16.61) in patients with median age of 67.5 years from two RCTs and in patients with median age of 67.5 (60 - 75), 71 (66 - 80+), 74.5 (65 - 89), 75 (66 - 81+) and 79.5 (60 - 99) from five cohort studies, respectively. Trastuzumab was significantly correlated with an increased risk of defined cardiac toxicities in five cohort studies (HR = 1.89, 95% CI 1.72 - 2.07, p < 0.00001) and two RCTs (HR = 3.00, 95% CI 1.71, 5.26, p < 0.00001). Sub-group analysis showed that the anthracycline-based chemotherapy increased the risk of CHF/HF and CM in patients among five cohort studies (HR = 2.16, 95% CI: 1.8 - 1.87, p < 0.00001). Conclusion: Trastuzumab is likely associated with an increased risk of cardiac toxicity in elderly patients with HER-2-positive breast cancer. Carefully monitoring cardiac function in elderly patients receiving trastuzumab, particularly with concurrent use of anthracycline, is warranted. © 2015 Taylor & Francis.


PubMed | China Medical University An Nan Hospital
Type: Journal Article | Journal: Biomedical reports | Year: 2015

The aim of the present study was to evaluate the association and prediction of dihydropyrimidine dehydrogenase gene (

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