Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment.

The ubiquitin-proteasome system (UPS) is essential for maintaining cell homeostasis by orchestrating the protein degradation, but is impaired in various diseases, including cancers. Several proteasome inhibitors, such as bortezomib, are currently used in cancer treatment, but associated toxicity limits their widespread application. Recently metal complex-based drugs have attracted great attention in tumor therapy; however, their application is hindered by low water-solubility and poor absorbency. Herein, we synthesized a new type of gold (I) complex named Na-AuPT, and further characterized its anticancer activity. Na-AuPT is highly water-soluble (6 mg/mL), and it was able to potently inhibit growth of a panel of 11 cancer cell lines (A549, SMMC7721, H460, HepG2, BEL7402, LNCap, PC3, MGC-803, SGC-7901, U266, and K562). In A549 and SMMC7721 cells, Na-AuPT (in a range of 2.5-20 µM) inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases. Furthermore, Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells, which was prevented by the metal chelator EDTA. Administration of Na-AuPT (40 mg · kg-1 · d-1, ip) in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo, accompanied by increased levels of total ubiquitinated proteins, cleaved caspase 3 and Bax protein in tumor tissue. Moreover, Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC50 value of 2.46 µM. We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy.

Association between the vascular endothelial growth factor gene polymorphisms and the risk of polycystic ovary syndrome in Northern Chinese women.

The present study aimed to investigate whether the single nucleotide polymorphisms (SNPs) rs2010963 and rs833061 in vascular endothelial growth factor (VEGF) gene is correlated with the risk of polycystic ovary syndrome (PCOS) in Northern Chinese women, as a preliminary study. This case-control study comprised 118 women with PCOS and 130 healthy women as controls. Genotyping of the two polymorphisms within the VEGF gene 5'-untranslated region and promoter region were performed using polymerase chain reaction ligase detection reaction method. The data showed that there was a significant difference in the genotype and allele distribution of the rs2010963 polymorphism between the PCOS group and the control group (p = .020 and .033, respectively). The women carrying the C allele (G/C + C/C genotype) had a lower risk of PCOS compared with the women with G/G genotype [odds ratio (OR = 0.55; 95% confidence interval (CI) = 0.33-0.91]. Our study shows for the first time that the rs2010963 polymorphism may be associated with a risk of PCOS in Northern Chinese women.

XPG Gene Polymorphisms and the Risk of Gastric Cardia Adenocarcinoma.

BACKGROUND: Polymorphisms in DNA repair genes can alter an individual's DNA repair capability and contribute to the risk of various cancers. AIMS: This study was designed to evaluate the association of single-nucleotide polymorphisms (SNPs) in the XPG gene with the risk of gastric cardia adenocarcinoma (GCA) in a high-incidence population in northern China. METHODS: Two SNPs from 431 GCA patients and 432 healthy controls were genotyped using the polymerase chain reaction/ligase detection reaction (PCR-LDR) method. RESULTS: The rs751402 C/T SNP T allele and the T/T genotype were associated with an increased risk of GCA in younger individuals (≤61 years) (odds ratio [OR] = 1.33 and 1.77, 95% confidence interval [CI] = 1.00-1.76 and 1.12-3.30, respectively). The rs873601 G/A SNP was not associated with susceptibility to GCA. CONCLUSIONS: Our findings indicate that the rs751402 C/T SNP has potential as a predictive marker for the risk of GCA and that carriers of the T/T genotype should receive periodic upper gastrointestinal fiber tests to facilitate the early detection and early treatment of GCA.

Genetic polymorphisms in the Fas and FasL genes are associated with epithelial ovarian cancer risk and clinical outcomes.

AIM: In this study, we evaluated whether functional polymorphisms within the Fas and FasL genes were associated with the risk of developing epithelial ovarian cancer (EOC) and survival of patients with EOC. METHODS: A case-control study was performed in 342 EOC patients and 344 control women. The genotypes of three promoter region polymorphisms (Fas -1377G/A, -670A/G and FasL -844T/C) were determined using ligase detection reaction-polymerase chain reaction (LDR-PCR). The clinical outcomes in 202 EOC patients were compared across genotypes. RESULTS: The genotype frequencies of the FasL -844 T/C polymorphism were significantly different between the case and control groups (P=0.034). Compared to the T/T and T/C genotypes, the C/C genotype significantly increased the risk of developing EOC (OR=1.46, 95% CI=1.08-1.99). The survival analysis showed that the Fas -1377G/A and -670A/G polymorphisms were related to prognosis in EOC patients. Compared with patients with the G/G genotype of the -1377G/A polymorphism, patients carrying the A allele had a shorter PFS and OS, as determined by univariate and multivariate analysis (HR=1.81, 95% CI=1.26-2.62 and HR=1.86, 95% CI=1.15-3.00, respectively). Similarly, Kaplan-Meier and Cox proportional hazard model analyses indicated that patients carrying the G allele of Fas -670A/G polymorphisms had shorter PFS and OS than those carrying the AA genotype (HR=1.67, 95% CI=1.15-2.42 and HR=1.80, 95% CI=1.10-2.94, respectively). CONCLUSIONS: Functional polymorphisms in the Fas and FasL genes may be involved in epithelial ovarian cancer development and progression in northern Chinese women.