Qinghua Xia

Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo

Valproic acid (VPA) is an established drug in the long-term therapy of seizure disorders. Recently, VPA has been associated with anticancer activity, an effect thought to be mediated through the inhibition of cellular histone deacetylase 1. We investigated the effect of various doses of VPA (0, 1.2, and 5.0 mmol/L) administered either acutely or chronically on histone acetylation, p21 gene expression, androgen receptor expression, prostate-specific antigen (PSA) expression, and cell survival and proliferation in prostate cancer cell lines. We also studied the effect of chronic VPA on tumor xenograft growth in vivo. Our results show that acute treatment (3 days) VPA can increase net histone H3 acetylation and up-regulate p21, AR, and cytosolic PSA expression. Interestingly, the effects on AR and PSA are reversed with chronic treatment. In addition, acute VPA reduces cell survival but has no effect on the subsequent proliferation of surviving cells following drug withdrawal. However, when VPA is chronically administered (10-14 days) to prostate cancer cells, even lower doses of VPA result in marked decreases in the net proliferation rate, correlating with increased caspase-2 and caspase-3 activation. These effects are evident in both androgen receptor-positive (LNCaP and C4-2) and androgen receptor-negative (DU145 and PC3) prostate cancer cells. Moreover, chronic VPA treatment results in statistically significant reduction of tumor xenograft growth in vivo. We conclude that acute treatment has nominal effects on prostate cancer cell survival and proliferation, but chronic VPA results in profound decreases in proliferation, independently of androgen regulation.

The association between metabolic syndrome and the risk of prostate cancer, high-grade prostate cancer, advanced prostate cancer, prostate cancer-specific mortality and biochemical recurrence

BackgroundAlthough a previous meta-analysis reported no association between metabolic syndrome (MetS) and prostate cancer risk, a number of studies suggest that MetS may be associated with the aggressiveness and progression of prostate cancer. However, these results have been inconsistent. This systematic review and meta-analysis investigated the nature of this association.MethodsWe systematically searched MEDLINE, EMBASE and bibliographies of retrieved studies up to January 2013 using the keywords “metabolic syndrome” and “prostate cancer”. We assessed relative risks (RRs) of the prostate cancer, several parameters of prostate cancer aggressiveness and progression associated with MetS using 95% confidence intervals (95% CIs).ResultsThe literature search produced 547 hits from which 19 papers were extracted for the meta-analysis. In cancer-free population with and without MetS, the combined adjusted RR (95% CI) of prostate cancer risk and prostate cancer-specific mortality in longitudinal cohort studies is 0.96 (0.85 ~ 1.09) and 1.12 (1.02 ~ 1.23) respectively. In the prostate cancer patients with and without MetS, the combined unadjusted OR (95% CI) of high grade Gleason prostate cancer is 1.44 (1.20 ~ 1.72), the OR of advanced prostate cancer is 1.37 (1.12 ~ 1.68) and the OR of biochemical recurrence is 2.06 (1.43 ~ 2.96).ConclusionsThe overall analyses revealed no association between MetS and prostate cancer risk, although men with MetS appear more likely to have high-grade prostate cancer and more advanced disease, were at greater risk of progression after radical prostatectomy and were more likely to suffer prostate cancer-specific death. Further primary studies with adjustment for appropriate confounders and larger, prospective, multicenter investigations are required.

Valproic acid induces autophagy by suppressing the Akt/mTOR pathway in human prostate cancer cells

Previous studies have demonstrated that the chronic administration of valproic acid (VPA) suppresses angiogenesis in vivo; however, the mechanisms implicated in VPA-induced autophagy remain unclear. The current study aimed to assess VPA-induced autophagy in three prostate cancer cell lines (PC3, DU145 and LNCaP), in addition to analyzing the Akt/mammalian target of rapamycin (mTOR) signal pathway. Prostate cancer cell lines were cultured with various doses of VPA. Cell cycle was analyzed using flow cytometry, and autophagy markers [1A/1B-light chain 3 (LC3)-II and Beclin-1] were examined using transmission electron microscopy, fluorescent microscopy and western blotting. Activation of the Akt/mTOR signal pathway was also assessed by western blotting. The results demonstrated that VPA induced autophagosomes and suppressed the Akt/mTOR signal pathway. This was confirmed by detection of increased LC3-II and Beclin-1 in VPA-treated cells compared with untreated controls. Phosphorylated forms of Akt (PC3, P=0.048; DU145, P=0.045; LNCaP, P=0.039) and mTOR (PC3, P=0.012; DU145, P=0.41; LNCaP, P=0.35) were significantly reduced following VPA treatment. These results suggest that VPA may function as a histone deacetylase inhibitor, suppressing the growth of prostate cancer cells by modulating autophagy pathways, including inhibition of the Akt/mTOR pathway. Further experiments are required to determine the significance of all involved pathways regarding VPA-induced growth inhibition.

Partial nephrectomy vs. radical nephrectomy for renal tumors: A meta-analysis of renal function and cardiovascular outcomes

OBJECTIVES The widespread use of partial nephrectomy (PN) has led to the preservation of functional renal parenchyma. However, the benefits of PN on renal function and cardiovascular outcomes remain controversial. Thus, a meta-analysis was performed to reconcile the conflicting results. MATERIALS AND METHODS PubMed, Embase, and the Cochrane Library were searched from inception to August 2015, and databases with all relevant comparative studies were included. The Mantel-Haenszel method with random-effects models was used to determine the pooled hazard ratios (HRs) for each outcome. RESULTS In total, 26 studies were pooled for new-onset chronic kidney disease, and 6 studies were pooled for cardiovascular outcomes. According to the pooled estimates, PN correlated with a 73% risk reduction of new-onset chronic kidney disease in all included patients (HR = 0.27, P<0.0001) and a 65% risk reduction in patients with tumors>4cm (HR = 0.35, P<0.0001) compared with radical nephrectomy. There were no significant differences between groups regarding postsurgery cardiovascular events (HR = 0.86, P = 0.238) and cardiovascular death (HR = 0.79, P = 0.196). Despite inherent selection biases, the pooled estimates were robust in sensitivity and subgroup analyses. CONCLUSIONS Our findings suggest that PN lowers the postoperative risk of new-onset chronic kidney disease. Nevertheless, the protection of renal function by PN did not reduce the risk of cardiovascular outcomes. However, this result remains controversial, and additional large-scale evaluations are warranted.

Immunotherapy of DC-CIK cells enhances the efficacy of chemotherapy for solid cancer: a meta-analysis of randomized controlled trials in Chinese patients

ObjectiveProfessional antigen-presenting dendritic cells (DCs) and cytokine-induced killer (CIK) cells, components of anti-cancer therapy, have shown clinical benefits and potential to overcome chemotherapeutic resistance. To evaluate whether DC-CIK cell-based therapy improves the clinical efficacy of chemotherapy, we reviewed the literature on DC-CIK cells and meta-analyzed randomized controlled trials (RCTs).MethodsWe searched several databases and selected studies using predefined criteria. RCTs that applied chemotherapy with and without DC-CIK cells separately in two groups were included. Odds ratio (OR) and mean difference (MD) were reported to measure the pooled effect.ResultsTwelve reported RCTs (826 patients), which were all performed on Chinese patients, were included. Combination therapy exhibited better data than chemotherapy: 1-year overall survival (OS) (OR=0.22, P<0.01), 2-year OS (OR=0.28, P<0.01), 3-year OS (OR=0.41, P<0.01), 1-year disease-free survival (DFS) (OR=0.16, P<0.05), 3-year DFS (OR=0.32, P<0.01), objective response rate (ORR) (OR=0.54, P<0.01), and disease control rate (DCR) (OR=0.46, P<0.01). Moreover, the levels of CD3+ T-lymphocytes (MD=−11.65, P<0.05) and CD4+ T-lymphocytes (MD=−8.18, P<0.01) of the combination group were higher.ConclusionsImmunotherapy of DC-CIK cells may enhance the efficacy of chemotherapy on solid cancer and induces no specific side effect. Further RCTs with no publishing bias should be designed to confirm the immunotherapeutic effects of DC-CIK cells.中文概要目的分析和研究DC-CIK细胞免疫治疗是否能够增强化疗在实体肿瘤中的疗效。创新点首次荟萃分析了关于DC-CIK细胞免疫治疗联合化疗治疗肿瘤疗效的随机对照试验, 并从多个角度对疗效进行综合评价。方法通过文献检索及筛选, 收集关于化疗联合DC-CIK细胞免疫治疗的随机对照试验 (图1), 并从中提取相关数据进行荟萃分析。总生存率 (OS) 、无病生存率 (DFS) 、客观缓解率 (ORR) 、疾病控制率 (DFS) 和治疗后T淋巴细胞亚型水平是本研究中的主要疗效指标, 比值比 (OR) (图3、4和5) 以及平均差 (MD) (图6) 用来评价各个指标的综合效应。结论共有12个随机对照试验被纳入我们的研究中 (表1和2) 。相对于单独应用化疗, DC-CIK细胞治疗联合化疗的综合疗法能在1年生存率、2年生存率、3年生存率、1年无病生存率、3年无病生存率、客观缓解率以及疾病控制率等指标上有明显优势, 且接受综合疗法患者的CD3+T淋巴细胞和CD4+T淋巴细胞水平明显更高。综上所述, DC-CIK细胞免疫治疗能够增强化疗对实体肿瘤的疗效。

Assessment of Tamsulosin as a Potential Male Contraceptive in Healthy Volunteers

OBJECTIVE To investigate the efficacy and safety of tamsulosin, an α(1A)-adrenoceptor antagonist, as a potential male contraceptive. METHODS Forty healthy male volunteers were equally divided into 2 groups, each of which received placebo and tamsulosin sequentially in a crossover manner. Ejaculatory profile was examined 4 to 6 hours after administration and adverse effects were noted. RESULTS Anejaculation occurred in all subjects after taking 0.8-mg of tamsulosin. Total functional sperm count was significantly reduced in subjects after taking 0.4-mg of tamsulosin. Six subjects receiving 0.8-mg of tamsulosin complained of tolerated discomfort, which disappeared 10 hours after administration. CONCLUSION When administered at 0.8 mg, tamsulosin can cause anejaculation with some transient side effects. Our results imply that tamsulosin and related drugs might potentially be used as male contraceptive agents in the future, which needs more studies to verify.

Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal

BackgroundMetformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC.MethodsWe performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-β, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-β /pSMAD3 and AMPK/AKT pathways.Results786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-β/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells.ConclusionsVPA not only exhibits synergistic cytotoxicity with metformin but also counteracts resistance to metformin in renal cell carcinoma cell. The re-sensitization to metformin induced by VPA in metformin-resistant cells may help treat renal cell carcinoma patients.

Long noncoding RNA SNHG16 contributes to the development of bladder cancer via regulating miR-98/STAT3/Wnt/β-catenin pathway axis: FENG et al.

This study aimed to investigate the role and the possible mechanism of the long noncoding small nucleolar RNA host gene 16 (SNHG16) in bladder cancer development. The expression of SNHG16 in the tumor tissues and plasma of patients with bladder cancer as well as bladder cancer cell lines was detected. T24 cells were then transfected with sh‐SNHG16 to further investigate the effects of suppression of SNHG16 on T24 cell proliferation, apoptosis, migration, and invasion. In addition, the regulatory relationships between SNHG16 and miR‐98 as well as the target of miR‐98 were explored. Besides, the association between SNHG16 and the Wnt/β‐catenin pathway was further elucidated. The SNHG16 expression was upregulated in the tumor tissues and plasma of patients with bladder cancer, as well as bladder cancer cells. Suppression of SNHG16 inhibited T24 cell proliferation, promoted apoptosis, and suppressed migration and invasion in vitro. In addition, SNHG16 negatively regulated miR‐98 expression and regulated the malignant behaviors of T24 cells through sponging miR‐98. Moreover, signal transducer and activator of transcription 3 (STAT3) was identified as a functional target of miR‐98, and miR‐98 regulated the malignant behaviors of bladder cancer cells by targeting STAT3. Besides, suppression of SNHG16 inhibited the activation of the Wnt/β‐catenin pathway, which was further regulated by miR‐98 and STAT3, indicating that the effects of SNHG16/miR‐98/STAT3 on T24 cells were achieved through the Wnt/β‐catenin pathway. Our findings reveal that long noncoding RNAs SNHG16 is upregulated in bladder cancer and contributes to the development of bladder cancer possibly via regulating the miR‐98/STAT3/Wnt/β‐catenin pathway axis. The SNHG16/miR‐98/STAT3/Wnt/β‐catenin pathway axis may provide a new strategy for bladder cancer treatment.

Valproic acid inhibits epithelial‑mesenchymal transition in renal cell carcinoma by decreasing SMAD4 expression

Renal cell carcinoma (RCC) is the most common malignancy in urogenital neoplasms worldwide. According to previous studies, valproic acid (VPA), an anticonvulsant drug, can suppress tumor metastasis and decrease the expression level of Mothers against decapentaplegic homolog 4 (SMAD4) and therefore may inhibit epithelial‑mesenchymal transition (EMT), which is responsible for cancer metastasis. However, the association between VPA, EMT and SMAD4 in RCC metastasis remains obscure. In the present study, it was demonstrated that in the RCC cell lines 786‑O and Caki‑1 treated with VPA, the neural (N)‑cadherin, vimentin and SMAD4 protein and mRNA levels were decreased, accompanied with an increase in expression of epithelial (E)‑cadherin. Silencing SMAD4 expression decreased the expression of EMT markers, including N‑cadherin and simultaneously upregulated E‑cadherin in RCC cell lines. SMAD4 overexpression counteracted the VPA‑mediated EMT‑inhibitory effect (P<0.05). The present study demonstrates that VPA inhibited EMT in RCC cells via altering SMAD4 expression. In addition, immunohistochemical staining demonstrated that transforming growth factor‑β (TGF‑β) and low expression of SMAD4 was associated with a lower Fuhrman grade and low expression of transcription intermediary factor 1‑γ was associated with a higher tumor Fuhrman grade (P<0.05), Therefore, based on the regulatory effect of SMAD4 on EMT‑associated transcription factors, SMAD4 which can form a SMAD3/SMAD4 complex induced by TGF‑β, could be a potential anticancer drug target inhibiting tumor invasion and metastasis in RCC.

449. Evaluation of New Generation of Prostate Specific Replication Competent Adenoviruses with E1A-AR Chimera

Adenoviral vector-based gene therapy has been evaluated as a potential therapeutic for prostate cancer. The prostate specific conditionally replication competent adenoviruses (CRADs) are designed to replicate and lyse the prostate epithelium under the control of the E1A gene expression by a prostate specific promoter. Recently we have determined that E1A inhibits the androgen receptor (AR) function, resulting in the attenuation of prostate specific CRAD vectors. We designed E1A-AR fusion chimeras in a new generation of prostate specific replication competent adenoviruses to overcome the inhibition of AR and restore efficient ARE-dependent E1A expression. A series of CRADs with chimeric E1A-AR were constructed and evaluated in prostate cancer cells and non-prostate cancer cells. Here, we describe the function of recombinant adenoviruses with E1A-AR chimeric expression in in vitro study.