The reversibility of non-genotoxic phenotypic changes has been explored in order to develop novel preventive and therapeutic approaches for cancer. Quisinostat (JNJ-26481585), a novel second-generation histone deacetylase inhibitor (HDACi), has efficient therapeutic actions on non-small cell lung cancer (NSCLC) cell. The present study aims at investigating underlying molecular mechanisms involved in the therapeutic activity of quisinostat on NSCLC cells. We found that quisinostat significantly inhibited A549 cell proliferation in dose- and time-dependent manners. Up-acetylation of histones H3 and H4 and non-histone protein α-tubulin was induced by quisinostat treatment in a nanomolar concentration. We also demonstrated that quisinostat increased reactive oxygen species (ROS) production and destroyed mitochondrial membrane potential (ΔΨm), inducing mitochondria-mediated cell apoptosis. Furthermore, exposure of A549 cells to quisinostat significantly suppressed cell migration by inhibiting epithelial-mesenchymal transition (EMT) process. Bioinformatics analysis indicated that effects of quisinostat on NSCLC cells were associated with activated p53 signaling pathway. We found that quisinostat increased p53 acetylation at K382/K373 sites, upregulated the expression of p21(Waf1/Cip1), and resulted in G1 phase arrest. Thus, our results suggest that the histone deacetylase can be a therapeutic target of NSCLC to discover and develop a new category of therapy for lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s10565-016-9347-8) contains supplementary material, which is available to authorized users.

This study aimed to evaluate the preoperative prognostic value of systemic inflammation response index and platelet-to-lymphocyte ratio (SIRI-PLR) in patients with upper tract urothelial carcinoma (UTUC). The prognostic ability of SIRI-PLR was evaluated in a training cohort comprising 259 patients with UTUC who underwent radical nephroureterectomy and was further validated in an independent cohort comprising of 274 patients. Multivariate Cox regression models showed that SIRI was significantly associated with overall-survival (OS), cancer-specific survival (CSS), and metastatic-free survival (MFS), and PLR significantly affected OS and CSS (all P < 0.05). In particular, a simultaneously high SIRI-PLR value was considered an independent risk factor even after adjusting for confounding factors and was superior to SIRI alone in predicting survival among patients with UTUC. The analyses of concordance-index and receiver operating characteristic curve showed that incorporation of SIRI-PLR vs. without its incorporation into newly developed nomograms or currently available clinical parameters, such as pathologic T stage, N stage, or tumor grade, had higher accuracy in predicting urologic outcomes of patients with UTUC. These results were observed in the training cohort and were confirmed in the validation cohort. In conclusion, patients with a simultaneously high SIRI-PLR value had significantly poor prognosis. Incorporating SIRI-PLR into currently available clinical parameters can help in patient management.

Background: Few studies focused on the relationship between the albumin-to-alkaline phosphatase ratio (AAPR) and the urologic outcomes in patients with non-metastatic renal cell carcinoma (RCC) following curative surgery. The aim of this study was to evaluate the prognostic value of preoperative AAPR in non-metastatic RCC patients. Methods: The prognostic value of AAPR was evaluated in a primary cohort with 419 non-metastatic RCC patients following curative radical or partial nephrectomy and then further validated in an independent cohort consisting of 204 patients. A nomogram was developed based on the independent predictors, and its predictive value was assessed. Results: Kaplan-Meier survival analysis demonstrated that patients with low AAPR levels were significantly associated with worse overall survival (OS) and cancer-specific survival (CSS) compared with patients with high AAPR levels both in two cohorts. Univariate and multivariate analyses revealed that low AAPR was an independent risk factor for OS (HR = 2.745; 95%CI, 1.266-5.953; P = 0.011) and CSS (HR = 3.042; 95%CI, 1.278-7.243; P = 0.012). Moreover, subgroup analysis (Fuhrman grade G1+G2 and Fuhrman grade G3+G4; T1+T2 stage and T3+T4 stage) revealed that low AAPR was also related to worse urological outcomes. Although no significant differences between patients with low AAPR and patients with high AAPR can be observed with regard to CSS under Fuhrman grade G1+G2 (P=0.058) and T1+T2 stage (P=0.318), there was a worse CSS trend in low AAPR patients. The established nomograms for OS and CSS were well calibrated and had moderate discriminative ability (concordance index: 0.821 and 0.839, respectively) Conclusions: Preoperative AAPR might be an independent prognostic factor in patients with non-metastatic RCC. The ratio should be applied in RCC patients for risk stratification and clinical decision-making.