Association of HIF-1α and NDRG2 Expression with EMT in Gastric Cancer Tissues.

OBJECTIVE: This study aims to investigate the differences in the expression of hypoxia-inducible factor-1α (HIF-1α), N-myc downstream-regulated gene 2 (NDRG2) and epithelial mesenchymal transition (EMT)-related proteins in normal gastric tissues, gastric cancer tissues and lymph node metastasis. METHODS: Immunohistochemistry was used to detect the expression of HIF-1α, NDRG2, E-cadherin, Snail and Twist in normal gastric tissues, gastric cancer tissues and lymph node metastasis. RESULTS: In normal gastric tissues, HIF-1α was not expressed, NDRG2 was highly expressed. There was a significant between the expression of NDRG2 and Snail, as well as of NDRG2 and Twist. In gastric cancer tissues, there was no statistically difference between the expression of HIF-1α and E-cadherin, NDRG2 and E-cadherin. However, there was a significant difference in expression between the expression of HIF-1α and Snail, HIF-1α and Twist, NDRG2 and Snail, and NDRG2 and Twist. In lymph node metastasis tissues, we show that HIF-1α was highly expressed, while NDRG2 was not, and the difference between the expression of HIF-1α and E-cadherin, HIF-1α and Snail, HIF-1α and Twist was not significant. CONCLUSION: HIF-1α may promote EMT, possibly by inhibiting the expression of NDRG2.

Phthalazino[1,2-b]quinazolinones as p53 Activators: Cell Cycle Arrest, Apoptotic Response and Bak-Bcl-xl Complex Reorganization in Bladder Cancer Cells.

p53 inactivation is a clinically defined characteristic for cancer treatment-nonresponsiveness. It is therefore highly desirable to develop anticancer agents by restoring p53 function.1 Herein the synthesized phthalazino[1,2-b]quinazolinones were discovered as p53 activators in bladder cancer cells. 10-Bromo-5-(2-dimethylamino-ethylamino)phthalazino[1,2-b]quinazolin-8-one (5da) was identified as the most promising candidate in view of both its anticancer activity and mechanisms of action. 5da exhibited strong anticancer activity on a broad range of cancer cell lines and significantly reduced tumor growth in xenograft models at doses as low as 6 mg/kg. Furthermore, 5da caused cell cycle arrest at S/G2 phase, induced apoptosis, changed cell size, and led to cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that accumulation of phospho-p53 in mitochondria after 5da treatment resulted in conformational activation of Bak, thereby evoking cell apoptosis, finally leading to irreversible cancer cell inhibition. Our present studies furnish new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent quinazolinone compound.

Arylurea Derivatives: A Class of Potential Cancer Targeting Agents.

Arylurea derivatives, an important class of small molecules, have received considerable attention in recent years due to their wide range of biological applications. Various molecular targeted agents with arylurea scaffold as potential enzyme/receptor inhibitors were constructed with the successful development of sorafenib and regorafenib. This review focuses on those arylureas possessing anti-cancer activities from 2010 to date. According to their different mechanisms of action, these arylureas are divided into the following six categories: (1) Ras/Raf/MEK/ERK signaling pathway inhibitors; (2) tumor angiogenesis inhibitors, their targets include Vascular Endothelial Growth Factor Receptors (VEGFRs), Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), Epidermal Growth Factor Receptors (EGFRs), Insulin-Like Growth Factor 1 Receptor (IGF-1R), Fmslike Tyrosine Kinase 3 (FLT3), c-Kit, MET, and Smoothened (Smo); (3) PI3K/AKT/mTOR signaling pathway inhibitors; (4) cell cycle inhibitors, their targets include Checkpoint Kinases (Chks), Cyclin- Dependent Kinases (CDKs), Aurora, SUMO activating enzyme 1 (SUMO E1), tubulin, and DNA; (5) tumor differentiation, migration, and invasion inhibitors, their targets include Matrix Metalloproteinases (MMPs), LIM kinase (Limk), Nicotinamide Phosphoribosyltransferase (Nampt), and Histone Deacetylase (HDAC); (6) arylureas from the rational modification of natural products. This review focuses on the Structure-Activity Relationships (SARs) of these arylureas. The structural evolution and current status of some typical anti-cancer agents used in clinic and/or in clinical trials are emphasized.

[Expression of cytochrome P450scc in human early placenta].

The present study has determined the cellular distribution of cytochrome P450scc in human early placenta by immunohistochemistry and assessed the abundances of cytochrome P450scc protein in the villous tissue at 6-9 weeks of human pregnancy by Western blotting. The results showed that immunoreactive P450scc was mainly localized in the villous syncytiotrophoblast cells but not in the cytotrophoblast cells and the villous core, and that the expression of protein for cytochrome P450scc in human early placental villous tissues increased gradually with advancing weeks of pregnancy. Taken together, these findings suggest that the syncytiotrophoblast cells are the major site expressing P450scc in human early placenta, and that increasing expression of cytochrome P450scc in placental villi might establish a foundation, in terms of enzymology, for site-shift of progesterone biosynthesis from the corpus luteum to the placenta during human early pregnancy.