Epigenetic regulation of angiogenesis in lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide, in which angiogenesis is highly required for lung cancer cell growth and metastasis. Genetic regulation of this multistep process is being studied extensively, however, relatively less is known about the epigenetic regulation of angiogenesis in lung cancer. Several epigenetic alterations contribute to regulating angiogenesis, such as epimodifications of DNA, posttranslational modification of histones, and expression of noncoding RNAs. Here, we review the current knowledge of the epigenetic regulation of angiogenesis and discuss the potential clinical applications of epigenetic-based anticancer therapy in lung cancer. Overall, epigenetic-based therapy will likely emerge as a prominent approach to treat lung cancer in the future.

Resveratrol Promotes Tumor Microvessel Growth via Endoglin and Extracellular Signal-Regulated Kinase Signaling Pathway and Enhances the Anticancer Efficacy of Gemcitabine against Lung Cancer.

The synergistic anticancer effect of gemcitabine (GEM) and resveratrol (RSVL) has been noted in certain cancer types. However, whether the same phenomenon would occur in lung cancer is unclear. Here, we uncovered the molecular mechanism by which RSVL enhances the anticancer effect of GEM against lung cancer cells both in vitro and in vivo. We established human lung adenocarcinoma HCC827 xenografts in nude mice and treated them with GEM and RSVL to detect their synergistic effect in vivo. Tumor tissue sections from nude mice were subjected to hematoxylin and eosin staining for blood vessel morphological observation, and immunohistochemistry was conducted to detect CD31-positive staining blood vessels. We also established the HCC827-human umbilical vein endothelial cell (HUVEC) co-culture model to observe the tubule network formation. Human angiogenesis antibody array was used to screen the angiogenesis-related proteins in RSVL-treated HCC827. RSVL suppressed the expression of endoglin (ENG) and increased tumor microvessel growth and blood perfusion into tumor. Co-treatment of RSVL and GEM led to more tumor growth suppression than treatment of GEM alone. Mechanistically, using the HCC827-HUVEC co-culture model, we showed that RSVL-suppressed ENG expression was accompanied with augmented levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 and increased tubule network formation, which may explain why RSVL promoted tumor microvessel growth in vivo. RSVL promoted tumor microvessel growth via ENG and ERK and enhanced the anticancer efficacy of GEM. Our results suggest that intake of RSVL may be beneficial during lung cancer chemotherapy.

Two new triterpenoids from Nauclea officinalis.

Two new triterpenoids and three 27-nor-triterpenoids were isolated from the stems (with bark) of Nauclea officinalis. Their structures were identified to be 2ß,3ß,19α,23-tetrahydroxy-urs-12-en-28-oic acid (1), 2ß,3ß,19α,23-tetrahydroxy-urs-12-en-28-O-[ß-D-glucopyranosyl (1-2)-ß-D-glucopyranosyl] ester (2), pyrocincholic acid 3ß-O-α-L-rhamnopyranoside (3), pyrocincholic acid 3ß-O-α-L-rhamnopyranosy 1-28-O-ß-D-glucopyranosyl ester (4), pyrocincholic acid 3ß-O-α-L-rhamnopyranosy1-28-O-ß-D-glucopyranosyl-(1-6)-ß-D-glucopyranosyl ester (5) by spectroscopic methods including 1D, 2D NMR and HR-MS analyses. The cytotoxic activity of 1-5 against lung cancer A-549 cells was also investigated.

Oldhamianoside II, a new triterpenoid saponin, prevents tumor growth via inducing cell apoptosis and inhibiting angiogenesis.

Oldhamianoside II is a new triterpenoid saponin that was isolated from the roots of Gypsophila oldhamiana. The present study aims to investigate the potential inhibitory activity of oldhamianoside II on tumor growth using an S180 tumor implantation mouse model. Oldhamianoside II at doses of 5.0 and 10.0 mg/kg was given with intraperitoneal injection for 10 days following subcutaneous inoculation of S180 tumor cells in anterior flank of mice. The tumor growth, the cell apoptosis, the microvessel density (MVD) in S180 tumors, the tumor cell viability, the tubular formation in vitro, and migration of tumor cells were examined. The expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and cyclooxygenase-2 (COX-2) was determined to analyze the associated mechanisms. The results showed that oldhamianoside II potently inhibited tumor cell viability in vitro. In addition, oldhamianoside II delayed tumor growth in anterior flank, induced S180 cell apoptosis, and reduced the MVD. Oldhamianoside II was also demonstrated to decrease the number of tubular structure and vessel formation in HUVEC cultures and chick embryo chorioallantoic membrane (CAM) model, respectively. Further study indicated that oldhamianoside II reduced the expression of VEGF, bFGF, and COX-2 in tumor sections. Moreover, oldhamianoside II inhibited the activity of migration and penetration to Matrigel of SGC7901 tumor cells in scratch wound and transwell chamber. In conclusion, our work defines oldhamianoside II, a new triterpenoid saponin, as a novel compound that can effectively inhibit S180 tumor growth, induce tumor cell apoptosis, prevent tumor angiogenesis, and inhibit cancer cell migration, suggesting that oldhamianoside II is a potential drug candidate for the treatment of cancer and for the prevention of metastasis.

A new triterpenoid saponin from Sanguisorba officinalis.

A new 19-oxo-18,19-seco-ursane-type triterpenoid saponin, named sanguisoside A (1), along with nine known triterpenoid saponins (2-10), was isolated from the roots of Sanguisorba officinalis. Their structures were determined on the basis of spectroscopic analysis and chemical method. Compounds 2 and 3 showed cytotoxic activity against SGC-7901, SMMC-7721, A549, and DU145 cell lines.

CIP-13F, a novel aminopeptidase N (APN/CD13) inhibitor, inhibits Lewis lung carcinoma growth and metastasis in mice.

PURPOSE: Aminopeptidase N (APN/CD13) is highly expressed on the surface of cancer cells and is thought to be involved in cancer growth and metastasis. The research of APN/CD13 inhibitors is considered as a strategy of cancer treatment. We aimed to evaluate the efficacy of CIP-13F, a novel APN/CD13 inhibitor, using a Lewis lung carcinoma (LLC) implantation mouse model. METHODS: C57BL/6 mice were subcutaneously inoculated with LLC cells in anterior flank. Then, 0, 50 and 100 mg/kg of CIP-13F were injected via vena caudalis. Bestatin was used as the positive control. Administration of CIP-13F or bestatin was performed daily for 3 consecutive weeks. Mice were killed, and the tumors in anterior flank and metastasis nodules in lungs were examined. The assays of immunohistochemical staining, immunofluorescent flow cytometry and western blotting were performed to estimate the expression of APN/CD13 in LLC cells. We carried out the experiments of Annexin-V/PI staining, DNA fragmentation analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining to determine apoptotic cells in LLC tissues. Using immunohistochemical staining with CD34, the antiangiogenesis of CIP-13F was evaluated in LLC tissue sections. RESULTS: CIP-13F treatment resulted in a significant delay of LLC growth in anterior flank. Examination of lungs showed that the number of metastatic nodules of LLC was also markedly decreased. The inhibitory effect of CIP-13F on LLC growth was further evidenced by the induction of LLC apoptosis, showing the increases in Annexin-V/PI staining cells, DNA fragmentation and TUNEL staining cells. Molecular analyses of LLC tissues in CIP-13F-treated mice suggested that the decrease in APN/CD13 expression by CIP-13F might account for its actions of mechanism. Further, the inhibition of angiogenesis in LLC tissues was determined, showing the decreases in microvessel density (MVD) and angiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and transforming growth factor-alpha (TGF-α). CONCLUSION: Our results showed that CIP-13F effectively inhibited LLC growth and pulmonary metastasis in mice and suggested that CIP-13F is a potential drug for the treatment for cancers with positive APN/CD13 expression.

Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) liriodenine with metal ions, and DNA binding studies.

Liriodenine (), an active component of the anticancer traditional Chinese medicine (TCM), was isolated from Zanthoxylum nitidum. Its reactions with Pt(II) and Ru(II) afforded three metal complexes: cis-[PtCl2(L)] (), cis-[PtCl2(L)(DMSO)] (), and cis-[RuCl2(L)(DMSO)2].1.5H2O (), the crystal structures of , and were determined by single-crystal X-ray diffraction methods. These complexes were fully characterized by elemental analysis, IR spectrophotometry, 1H and 13C NMR spectroscopies, and ES mass spectrometry. The in vitro cytotoxicity of and complexes against 11 human tumour cell lines was assayed. The metal-based compounds exhibit enhanced cytotoxicity vs. free , suggesting that these compounds display synergy in the combination of metal ions and liriodenine. The binding properties of and its complexes to ct-DNA were investigated through UV-vis, fluorescence, CD spectra, viscosity and agarose gels electrophoretic measurements.

[Pharmacokinetics study on yinhuang compound microenema in rabbits].

OBJECTIVE: To determine the parameters of pharmacokinetics in rabbits, and to provide a scientific basis for clinical application of Yinhuang compound microenema. METHOD: HPLC was used to determine the concentrations of chlorogenic acid and baicalin in the plasma samples of rabbits, then analyze these data by the pharmacokinetics program 3P97 to determine the parameters of pharmacokinetics and the compartmental model of both ingredients in Yinhuang compound microenema. RESULT: Baicalin showed two compartment model in rabbits and the main parameters of pharmacokinetics were as follows: t(1/2)alpha of 0.311 h, t(1/2)beta of 1.640 h, AUC of 1.531 x 10(-2) g x h x L(-1), tmax of 0.287 h, Vd of 2.182 L. Chlorogenic acid showed two compartment model in rabbits and the main parameters of pharmacokinetics were as follows: t(1/2)alpha of 0.324 h, t(1/2)beta of 1.206 h, AUC of 2.135 x 10(-2) g x h x L(-1), tmax of 0.317 h,Vd of 2.251 L. CONCLUSION: The main components in Yinhuang compound microenema baicalin and chlorogenic acid are absorbed quickly and absolutely after rectal administration, which have good characters of pharmacokinetics.