Shang-Sen Lee

CCL2 increases αvβ3 integrin expression and subsequently promotes prostate cancer migration.

BACKGROUND Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family which is associated with the disease status and outcomes of cancers. Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. However, the effect of CCL2 on human prostate cancer cells is largely unknown. The aim of this study was to examine the role of CCL2 in integrin expression and migratory activity in prostate cancers. METHODS Prostate cancer migration was examined using Transwell, wound healing, and invasion assay. The PKCδ and c-Src phosphorylations were examined by using western blotting. The qPCR was used to examine the mRNA expression of integrins. A transient transfection protocol was used to examine AP-1 activity. RESULTS Stimulation of prostate cancer cell lines (PC3, DU145, and LNCaP) induced migration and expression of integrin αvβ3. Treatment of cells with αvβ3 antibody or siRNA abolished CCL2-increased cell migration. CCL2-increased migration and integrin expression were diminished by CCR2 but not by CCR4 inhibitors, suggesting that the CCR2 receptor is involved in CCL2-promoted prostate cancer migration. CCL2 activated a signal transduction pathway that includes PKCδ, c-Src, and AP-1. Reagents that inhibit specific components of this pathway each diminished the ability of CCL2 to effect cell migration and integrin expression. CONCLUSIONS Interaction between CCL2 and CCR2 enhances migration of prostate cancer cells through an increase in αvβ3 integrin production. GENERAL SIGNIFICANCE CCL2 is a critical factor of prostate cancer metastasis.

D-pinitol Inhibits Prostate Cancer Metastasis through Inhibition of αVβ3 Integrin by Modulating FAK, c-Src and NF-κB Pathways

Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. D-pinitol, a 3-methoxy analogue of d-chiro-inositol, was identified as an active principle in soy foods and legumes, and it has been proven to induce tumor apoptosis and metastasis of cancer cells. In this study, we investigated the anti-metastasis effects of D-pinitol in human prostate cancer cells. We found that D-pinitol reduced the migration and the invasion of prostate cancer cells (PC3 and DU145) at noncytotoxic concentrations. Integrins are the major adhesive molecules in mammalian cells and have been associated with the metastasis of cancer cells. Treatment of prostate cancer cells with D-pinitol reduced mRNA and cell surface expression of αvβ3 integrin. In addition, D-pinitol exerted its inhibitory effects by reducing focal adhesion kinase (FAK) phosphorylation, c-Src kinase activity and NF-κB activation. Thus, D-pinitol may be a novel anti-metastasis agent for the treatment of prostate cancer metastasis.

Potential Therapeutic Roles of Tanshinone IIA in Human Bladder Cancer Cells

Tanshinone IIA (Tan-IIA), one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. Here we explored the anticancer effect of Tan-IIA in human bladder cancer cell lines. Our results showed that Tan-IIA caused bladder cancer cell death in a time- and dose-dependent manner. Tan-IIA induced apoptosis through the mitochondria-dependent pathway in these bladder cancer cells. Tan-IIA also suppressed the migration of bladder cancer cells as revealed by the wound healing and transwell assays. Finally, combination therapy of Tan-IIA with a lower dose of cisplatin successfully killed bladder cancer cells, suggesting that Tan-IIA can serve as a potential anti-cancer agent in bladder cancer.

Use of 5-Alpha-Reductase Inhibitors Did Not Increase the Risk of Cardiovascular Diseases in Patients with Benign Prostate Hyperplasia: A Five-Year Follow-Up Study

Background This nationwide population-based study investigated the risk of cardiovascular diseases after 5-alpha-reductase inhibitor therapy for benign prostate hyperplasia (BPH) using the National Health Insurance Research Database (NHIRD) in Taiwan. Methods In total, 1,486 adult patients newly diagnosed with BPH and who used 5-alpha-reductase inhibitors were recruited as the study cohort, along with 9,995 subjects who did not use 5-alpha-reductase inhibitors as a comparison cohort from 2003 to 2008. Each patient was monitored for 5 years, and those who subsequently had cardiovascular diseases were identified. A Cox proportional hazards model was used to compare the risk of cardiovascular diseases between the study and comparison cohorts after adjusting for possible confounding risk factors. Results The patients who received 5-alpha-reductase inhibitor therapy had a lower cumulative rate of cardiovascular diseases than those who did not receive 5-alpha-reductase inhibitor therapy during the 5-year follow-up period (8.4% vs. 11.2%, P=0.003). In subgroup analysis, the 5-year cardiovascular event hazard ratio (HR) was lower among the patients older than 65 years with 91 to 365 cumulative defined daily dose (cDDD) 5-alpha-reductase inhibitor use (HR=0.63, 95% confidence interval (CI) 0.42 to 0.92; P=0.018), however there was no difference among the patients with 28 to 90 and more than 365 cDDD 5-alpha-reductase inhibitor use (HR=1.14, 95% CI 0.77 to 1.68; P=0.518 and HR=0.83, 95% CI 0.57 to 1.20; P=0.310, respectively). Conclusions 5-alpha-reductase inhibitor therapy did not increase the risk of cardiovascular events in the BPH patients in 5 years of follow-up. Further mechanistic research is needed.

5-alpha-reductase inhibitors and the risk of diabetes mellitus: A nationwide population-based study.

This nationwide population‐based study investigated the risk of type 2 diabetes mellitus (DM) after 5‐alpha‐reductase inhibitor (5ARI) therapy for benign prostate hyperplasia (BPH) using the National Health Insurance Research Database (NHIRD) in Taiwan.

Maximum Urine Flow Rate of Less than 15ml/Sec Increasing Risk of Urine Retention and Prostate Surgery among Patients with Alpha-1 Blockers: A 10-Year Follow Up Study.

Background The aim of this study was to determine the subsequent risk of acute urine retention and prostate surgery in patients receiving alpha-1 blockers treatment and having a maximum urinary flow rate of less than 15ml/sec. Methods We identified patients who were diagnosed with benign prostate hyperplasia (BPH) and had a maximum uroflow rate of less than 15ml/sec between 1 January, 2002 to 31 December, 2011 from Taiwan’s National Health Insurance Research Database into study group (n = 303). The control cohort included four BPH/LUTS patients without 5ARI used for each study group, randomly selected from the same dataset (n = 1,212). Each patient was monitored to identify those who subsequently developed prostate surgery and acute urine retention. Results Prostate surgery and acute urine retention are detected in 5.9% of control group and 8.3% of study group during 10-year follow up. Compared with the control group, there was increase in the risk of prostate surgery and acute urine retention in the study group (HR = 1.83, 95% CI: 1.16 to 2.91) after adjusting for age, comorbidities, geographic region and socioeconomic status. Conclusions Maximum urine flow rate of less than 15ml/sec is a risk factor of urinary retention and subsequent prostate surgery in BPH patients receiving alpha-1 blocker therapy. This result can provide a reference for clinicians.

CHADS2 scores as a predictor of ischemic stroke after radical prostatectomy

Patients with prostate cancer have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. The Charlson Comorbidity Index Score (CCIS) is a widely accepted measure for risk adjustment in administrative claims data sets. This study assesses the predictive value of CHADS2 scores and CCIS for stroke among patients with prostate cancer. The study was conducted based on data taken from Taiwans National Health Insurance Research Database (NHIRD). We identified a total of 5414 participants with nonatrial fibrillation (AF) prostate cancer diagnoses who underwent radical prostatectomy between 1997 and 2011. CHADS2 scores and CCIS were used to stratify the 5‐year ischemic stroke risk. All participants were followed from the date of enrollment until ischemic stroke, death, or the end of the 5‐year follow‐up period. The 5‐year risk of ischemic stroke in the present study was 1.7%. Ischemic stroke has a better correlation with CHADS2 (CHADS2 score = 0 to 1: 0.02%, CHADS2 score = 2 to 3: 13.9%, CHADS2 score ≥ 4: 44.4%; AUC = 0.978) than CCIS (CCIS = 0 to 1: 1.6%, CCIS = 2 to 3: 1.7%, CCIS ≥ 4: 3.8%; AUC = 0.520). Our results show that patients with prostate cancer who underwent radical prostatectomy show significantly higher risk of ischemic stroke in high CHADS2 score patients, and the CHADS2 score could be applied for ischemic stroke prediction. Cardiovascular risks evaluation and management are suggested for prostate cancer patients with higher CHADS2 score.

Assessment of the charlson comorbidity index score, CHADS2 and CHA2DS2-VASc scores in predicting death in patients with thoracic empyema

Background Patients with thoracic empyema have an increased risk of mortality, but their absolute rate of mortality depends on age and comorbidities. Objective This study seeks to assess the predictive value of the Charlson Comorbidity Index score (CCIS), CHADS2 and CHA2DS2‐VASc scores for mortality risk in patients with empyema thoracis. Methods From Taiwans National Health Insurance Research Database we identified a total of 484 participants diagnosed with thoracic empyema. The CCIS, CHADS2 and CHA2DS2‐VASc scores were used to stratify mortality risk. Results The incidence rate of mortality in the present study was 20.39 per 1000 person‐months. A strong correlation was found between thoracic empyema and CCIS score. Conclusions Our results show that patients with thoracic empyema have a significantly high incidence rate of mortality and that CCIS can be used as an indicator of risk for mortality.

5-alpha-reductase inhibitor therapy postpones urine retention and prostate surgery in patients with prostate enlargement and a maximum uroflow rate of less than 15 ml/sec

Background This study investigated the risk of transurethral resection of prostate (TURP) and acute urine retention (AUR) in relation to 5-alpha-reductase inhibitor (5ARI) therapy. Methods We identified 22,687 patients who were newly diagnosed with PE and low urinary tract symptoms (LUTS) between January 1, 2002 and December 31, 2011. We further classified study subjects who had moderate to severe LUTS and a maximum uroflow rate of less than 15ml/sec into three groups by their defined daily dose (DDD) of 5ARI used. The control group consisted of 7–28 cumulative DDD (cDDD) 5ARI users, while the short-term treatment group was 29-179cDDD 5ARI users, and the long-term treatment group was users of more than 180cDDD 5ARI. Each patient was monitored to identify those who subsequently developed TURP and AUR. Results TURP and AUR are detected in 5.6% of control group, 7.6% of short-term treatment group and 5.5% of long-term treatment group during 10-year follow up. Compared with the control group, there was no difference in the risk of TURP and AUR in the short-term and long-term treatment groups (HR = 1.41, 95% CI 0.76 to 2.62 and HR = 0.81, 95% CI 0.42 to 1.56, respectively). Conclusion 5ARI therapy did not change the risk of TURP and AUR events in patients with PE, moderate to severe LUTS and a maximum uroflow rate of less than 15 ml/sec in 10 years of follow-up. But long-term 5ARI used can postpone AUR and TURP for 8.16 months.