Suberoylanilide hydroxamic acid overcomes erlotinib-acquired resistance via phosphatase and tensin homolog deleted on chromosome 10-mediated apoptosis in non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib, are widely used to treat non-small cell lung cancer (NSCLC). However, acquired resistance is unavoidable, impairing the anti-tumor effects of EGFR-TKIs. It is reported that histone deacetylase (HDAC) inhibitors could enhance the anti-tumor effects of other antineoplastic agents and radiotherapy. However, whether the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) can overcome erlotinib-acquired resistance is not fully clear. METHODS: An erlotinib-resistant PC-9/ER cell line was established through cell maintenance in a series of erlotinib-containing cultures. NSCLC cells were co-cultured with SAHA, erlotinib, or their combination, and then the viability of cells was measured by the 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and apoptosis was determined by flow cytometry and western blotting. Finally, the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was assessed by western blotting. RESULTS: The half-maximal inhibitory concentration of parental PC-9 cells was significantly lower than the established erlotinib-acquired resistant PC-9/ER cell line. PC-9/ER cells demonstrated reduced expression of PTEN compared with PC-9 and H1975 cells, and the combination of SAHA and erlotinib significantly inhibited cell growth and increased apoptosis in both PC-9/ER and H1975 cells. Furthermore, treating PC-9/ER cells with SAHA or SAHA combined with erlotinib significantly upregulated the expression of PTEN mRNA and protein compared with erlotinib treatment alone. CONCLUSIONS: PTEN deletion is closely related to acquired resistance to EGFR-TKIs, and treatment with the combination of SAHA and erlotinib showed a greater inhibitory effect on NSCLC cells than single-drug therapy. SAHA enhances the suppressive effects of erlotinib in lung cancer cells, increasing cellular apoptosis and PTEN expression. SAHA can be a potential adjuvant to erlotinib treatment, and thus, can improve the efficacy of NSCLC therapy.

Cumulative Score Based on Preoperative Fibrinogen and Pre-albumin Could Predict Long-term Survival for Patients with Resectable Gastric Cancer.

Background: To investigate the prognostic significance of the cumulative score based on preoperative fibrinogen and pre-albumin (FP score) in patients with gastric cancer after radical gastrectomy. Methods: Baseline characteristics, preoperative fibrinogen and pre-albumin levels were retrospectively reviewed in patients who underwent radical gastrectomy. The optimal cut-off values for fibrinogen and pre-albumin were defined as 4.0 g/L and 230.0 mg/L, respectively. Patients with elevated fibrinogen (≥ 4.0 g/L) and decreased pre-albumin (< 230.0 mg/L) levels were allocated an FP score of 2, those with only one of these two abnormalities were assigned a score of 1, and those with neither of the two abnormalities were allocated a score of 0. The prognostic value was examined by univariate and multivariate regression analyses. Results: The preoperative FP score was significantly correlated with age, tumor size, fibrinogen level, pre-albumin level and white blood cell count. No significant differences based on sex, tumor location, degree of differentiation, depth of invasion, lymph node status, tumor-node-metastasis (TNM) stage or adjuvant chemotherapy were identified between the groups. In addition, univariate survival analysis revealed that a high preoperative FP score was significantly associated with unfavorable disease-free survival (DFS) [hazard ratio (HR), 1.482; 95% confidence interval (CI), 1.222-1.796; P < 0.001] and overall survival (OS) (HR, 1.623; 95% CI, 1.315-2.002; P < 0.001). Moreover, after adjusting for other factors, a high preoperative FP score remained an independent predictor for impaired DFS (HR, 1.434; 95% CI, 1.177-1.747; P < 0.001) and OS (HR, 1.413; 95% CI, 1.136-1.758; P = 0.002) in multivariate Cox regression analysis. Conclusions: The preoperative FP score significantly predicts long-term survival for gastric cancer patients who have undergone radical gastrectomy.

[Prognostic Value of CD14+HLA-DRlow/- Myeloid Derived Suppressor Cells in Diffuse Large B Cell Lymphoma].

OBJECTIVE: To investigate the role of myeloid-derived suppressor cells (MDSC) in the prognosis of patients with diffuse large B cell lymphoma (DLBCL). METHODS: The peripheral blood of 52 DLBCL patients and 30 healthy volunteers was collected. The CD14+HLA-DRlow/- was used as the immune marker for MDSC. The role of MDSC in the prognosis of DLBCL patients was analyzed by combination with the related clinicopathological data. RESULTS: The proportion of MDSC in peripheral blood of newly diagnosed DLBCL patients increased significantly (P＜0.01). The expression of MDSC in DLBCL patients was related with clinical staging, lactate dehydrogenase (LDH) level and IPI score (P＜0.01). There was no significant correlation with sex, age, and B symptoms. Univariate analysis showed that the clinical stage, serum LDH level, IPI score and MDSC level were the adverse factors affecting the overall survival (OS). Multivariate analysis showed that IPI score and MDSC level were independent risk factors for OS in DLBCL patients. CONCLUSION: MDSC can be used as an important index to evaluate the prognosis of DLBCL patients, contributing to evaluate the immune and tumor microenvironment of DLBCL patients.

Association between circulating leptin concentration and G-2548A gene polymorphism in patients with breast cancer: a meta-analysis.

INTRODUCTION: The aim of this meta-analysis was to summarize the evidence on the serum/plasma leptin concentrations in breast cancer (BC) patients, as well as the associations between leptin G-2548A gene polymorphisms and susceptibility to BC. MATERIAL AND METHODS: Potentially relevant studies about serum/plasma leptin levels and leptin G-2548A gene polymorphism were selected using the electronic databases PubMed, EMBASE and The Cochrane Library (from January 1 1995 to Jun 30 2017, no language restrictions). The potential sources of heterogeneity were assessed by the Q statistic and quantified using I2 ; publication bias was qualitatively assessed by funnel plot and quantitatively assessed by Egger's linear regression test. RESULTS: A total of 1141 articles were retrieved after database searches, and 27 studies with 9516 subjects (4542 BC patients/4974 controls) were finally included. The results indicated that BC patients had significantly higher leptin levels compared with healthy controls (SMD = 1.65, 95% CI: 1.21-2.09, p < 0.001), but there was no association between leptin G-2548A polymorphism and BC (OR = 1.05, 95% CI: 0.80-1.39, p = 0.722). Subgroup analyses demonstrated increased leptin levels in BC patients of different region, race, body mass index and waist circumference. CONCLUSIONS: Our results revealed a significantly higher leptin level in BC patients than in healthy controls, but no association between leptin G-2548A polymorphism and BC susceptibility was found.

Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt.

BACKGROUND: The Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) is implicated in diabetes, arthrosclerosis, and cancer. However, the role of SHIP2 in human gastric cancer remains unclear. METHODS: The expression levels of SHIP2 in gastric cancer tissues, a panel of gastric cancer cell lines, and normal gastric epithelial cells were analyzed by immunohistochemistry (IHC), Western blot, and real-time quantitative RT-PCR (qRT-PCR). Gastric cancer cells with either overexpressed SHIP2 or co-overexpressed SHIP2 and Akt were analyzed to determine cell proliferation, colony formation, apoptosis, cell migration, and invasion assays. Normal gastric epithelial cells with knockdown SHIP2 or co-knockdown SHIP2 and Akt were subjected by anchorage-independent growth assays. The effect of SHIP2 on tumor growth in vivo was detected by xenograft tumorigenesis assays. RESULTS: SHIP2 was commonly downregulated in gastric cancer compared with normal gastric mucosa, and overexpression of SHIP2 inhibited cell proliferation, induced apoptosis, suppressed cell motility and invasion in gastric cancer cells in vitro, and retarded the growth of xenograft gastric tumors in vivo, while knockdown of SHIP2 in normal gastric epithelial cells promoted anchorage-independent growth. Moreover, overexpression of SHIP2 inactivated Akt, and upregulated p21, p27, and the pro-apoptotic protein Bim. Restoring Akt activation in gastric cancer cells largely blocked the inhibition of PI3K/Akt signaling by SHIP2 and reversed the inhibitory effect of SHIP2 on tumorigenesis and proliferation. CONCLUSIONS: This study demonstrates, for the first time, that SHIP2 is frequently downregulated in gastric cancer, and reduced SHIP2 expression promotes tumorigenesis and proliferation of gastric cancer via activation of the PI3K/Akt signaling.

Targeting interleukin-22 in psoriasis.

Interleukin-22 (IL-22) is an IL-10 family cytokine that was recently discovered to be released by T helper 17 (Th17) cells, Th22 cells, etc. Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of psoriasis. For instance, IL-22 can inhibit keratinocyte terminal differentiation and can induce psoriasis-like epidermis alterations; serum IL-22 levels were correlated with the disease severity of psoriasis patients, and IL-22 mRNA was positively expressed in the psoriatic skin lesions, but negatively expressed in the normal controls. All these findings suggest that IL-22 may be implicated in psoriasis; therapeutics targeting IL-22 may have promise as a potential therapeutic target for treating psoriasis. In the present review, we summarize recent advances on the role of IL-22 in the pathogenesis and treatment of psoriasis.

MicroRNAs as promising biomarkers for gastric cancer.

Despite promising developments of treatment, the overall outcome of gastric cancer (GC) remains poor. Current tumor markers are not ideal due to relatively low sensitivity and specificity. There is an urgent need for identifying more specific and more sensitive novel markers in the clinical management of GC. MicroRNAs (miRNAs) are non-coding RNA molecules. Recently, miRNA studies have quickly moved from basic molecular research of cancer to areas of clinical application. On the basis of recent data, the present review mainly summarizes the potential role of miRNAs as molecular biomarkers for disease susceptibility, diagnosis, prognosis and drug-response prediction in GC. This review also highlights the miRNA expression profiles in GC and their relation to cancer classification and subtype stratification. Although there are still many challenges in the research field of tumor-related miRNAs, the small molecules will definitely improve the clinical management of GC in the future.

Effect of lumiracoxib on proliferation and apoptosis of human nonsmall cell lung cancer cells in vitro.

BACKGROUND: Lumiracoxib is a highly selective cyclooxygenase-2 (COX-2) inhibitor with antiinflammatory, analgesic and antipyretic activities comparable with class specific drugs, but with much improved gastrointestinal safety. No studies have examined lumiracoxib for antitumorigenic activity on human nonsmall cell lung cancer cell lines in vitro or its possible molecular mechanisms. METHODS: The antiproliferative effect of lumiracoxib alone or combined with docetaxol on A549 and NCI-H460 lines was assessed by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Drug-drug interactions were analyzed using the coefficient of drug interaction (CDI) to characterize the interactions as synergism, additivity or antagonism. Morphological changes were observed by acridine orange fluorescent staining. Extent of apoptosis was determined by flow cytometry. RESULTS: Lumiracoxib (15 - 240 micromol/L) has an inhibitory effect on the proliferation of A549 and NCI-H460 cell lines in concentration- and time-dependent manners with the IC50 values of 2597 micromol/L and 833 micromol/L, respectively. The synergistic effect was prominent when lumiracoxib (15 - 240 micromol/L) was combined with docetaxol (0.2 - 2 micromol/L) (CDI < 1). Fluorescent staining showed that lumiracoxib could induce apoptosis in A549 and NCI-H460 cells. Lumiracoxib treatment also caused an increase of the sub-G1 fraction in each cell line and resulted in an increase of G0/G1-phase cells and a decrease of S-phase cells. CONCLUSIONS: Lumiracoxib had antiproliferative effect on the human nonsmall cell lung cancer cell lines A549 and NCI-H460 and had a significant synergy with docetaxol, which may be related to apoptotic induction and cell cycle arrest.