Apatinib regulates the cell proliferation and apoptosis of liver cancer by regulation of VEGFR2/STAT3 signaling.

Liver cancer is the third most common cause of cancer related death worldwide. Apatinib showed satisfactory efficacy in various types of cancers, including breast cancer, malignant fibrous histiocytoma and liver cancer. However, how did Apatinib function in liver cancer is largely unknown. mRNA levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) as well as protein levels of VEGF and p-VEGFR2 were obviously higher in liver cancer cell line SMCC7721 than in normal liver cell LO2. Apatinib significantly inhibited the mRNA levels of VEGF and VEGFR2 as well as protein levels of VEGF and p-VEGFR2 compared with those in control group. At 12, 24 and 48 h after corresponding treatments, compared with the control group, Apatinib significantly lowered the cell viability of SMCC7721 cells, while transfection of si-signal transducer and activator of transcription 3 (siSTAT3) further augmented the effects of Apatinib. At 48 h after treatment, compared with the control group, Apatinib significantly upregulated the cell apoptosis rate of SMCC7721 cells, which was further induced by the transfection of siSTAT3. Compared with control group, Apatinib significantly induced BAX/Bcl-2 ratio elevation, reduced p-STAT3 and p-VEGFR2 expression, which were significantly augmented by the treatment of siSTAT3. In conclusion, Apatinib inhibited the cell proliferation and promoted the cell apoptosis of liver cancer by inhibiting the activation of VEGFR2/STAT3.

Antitumor effects of beta-amyrin in Hep-G2 liver carcinoma cells are mediated via apoptosis induction, cell cycle disruption and activation of JNK and P38 signalling pathways.

PURPOSE: Liver cancer is one of the major causes of cancer related deaths throughout the world and the fifth most common type of malignancy in men and eighth in women. Beta-amyrin has been reported to exhibit significant pharmacological properties and in the present study we examined the anticancer and apoptotic effects of beta-amyrin against Hep-G2 liver cancer cells. METHODS: The antiproliferative activity of beta-amyrin was determined by MTT assay. Apoptosis was assessed by DAPI staining and DNA damage was checked by the comet assay. The cell cycle analysis was carried out by flow cytometry and protein expression was examined by western blotting. RESULTS: Beta-amyrin exhibited significant anticancer activity against Hep-G2 cancer with IC50 values of 25 µM. The anticancer effects were attributed to induction of apoptosis and G2/M cycle arrest in a dose-dependent manner. Moreover, beta-amyrin could also activate the p38 and JNK signalling pathways. CONCLUSION: Based on the results of the current study, we propose that beta-amyrin may prove an important lead molecule for the treatment of liver cancer.

Curcumin inhibits tumor epithelial­mesenchymal transition by downregulating the Wnt signaling pathway and upregulating NKD2 expression in colon cancer cells.

Tumor invasion and metastasis are closely associated with epithelial­mesenchymal transition (EMT). EMT refers to epithelial cells under physiological and pathological conditions that are specific to mesenchymal transition. Curcumin inhibits EMT progression via Wnt signaling. The Wnt signaling pathway is a conservative EMT­related signaling pathway that is involved in the development of various tumors. In the present study, MTS assays were employed to analyze the proliferation of curcumin­treated cells. Naked cuticle homolog 2 (NKD2), chemokine receptor 4 (CXCR4) and antibodies associated with EMT were examined in SW620 colorectal cancer cell lines using western blot analysis and real­time qPCR. NKD2 small­interfering RNA (siRNA) and CXCR4 expression plasmid was synthesized and transfected into the colorectal cancer cell lines, and NKD2 and CXCR4 expression levels were detected. The results showed that curcumin significantly inhibited the proliferation of colorectal cancer cells and upregulated the expression of NKD2 in SW620 colorectal cancer cells and in the xenograft, resulting in the downregulation of key markers in the Wnt signaling. In addition, the progression of ETM was inhibited due to the overexpression of E­cadherin as well as the downregulation of vimentin. Curcumin also inhibited tumor metastasis by downregulating the expression of CXCR4 significantly. The results suggested involvement of the NKD2­Wnt­CXCR4 signaling pathway in colorectal cancer cells. In addition, curcumin is inhibit this signaling and the development of colorectal cancer.

Discovery of oral and inhaled PDE4 inhibitors.

The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.

Structural modifications of a 3-methoxy-2-aminopyridine compound to reduce potential for mutagenicity and time-dependent drug-drug interaction.

(S)-1-((4-(3-(6-Amino-5-methoxypyridin-3-yl)-1-isopropyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)propan-2-ol, 1, was recently identified as a potent inhibitor of the oncogenic kinase bRAF. Compounds containing 3-methoxy-2-aminopyridine, as in 1, comprised a promising lead series because of their high ligand efficiency and excellent ADME profile. However, following metabolic oxidation, compounds in this series also demonstrated two significant safety risks: mutagenic potential and time-dependent drug-drug interaction (TDI). Metabolite identification studies revealed formation of a reactive metabolite. We hypothesized that minimizing or blocking the formation of such a metabolite would mitigate the safety liabilities. Our investigation demonstrated that structural modifications which either reduced the electron density of the 3-methoxy-2-aminopyridine ring or blocked the reactive site following metabolic oxidation were successful in reducing TDI and AMES mutagenicity.

Discovery of oxazole-based PDE4 inhibitors with picomolar potency.

Optimization of oxazole-based PDE4 inhibitors has led to the discovery of a series of quinolyl oxazoles, with 4-benzylcarboxamide and 5-α-aminoethyl groups which exhibit picomolar potency against PDE4. Selectivity profiles and in vivo biological activity are also reported.

Association between C3orf21, TP63 polymorphisms and environment and NSCLC in never-smoking Chinese population.

Recently, two genome-wide association studies in Asia identified gene polymorphisms known as rs4488809, rs9816619 in TP63 and rs2131877, rs952481 in C3orf21. It has been proposed that these polymorphisms are susceptibility loci for non-small cell lung cancer (NSCLC) development among Japanese and Korean populations. We ask whether susceptibility to NSCLC is limited to the Chinese population or whether the environment also affects genetic polymorphisms. We conducted a matched case-control study to explore this question. Results show that polymorphism of TP63 was not associated with NSCLC development, whereas variant genotypes of C3orf21 were nominally associated with a reduced risk of lung adenocarcinoma (OR=0.619, 95% CI=0.390-0.976). These results strongly suggest that environmental agents interact with human genetic polymorphism independent of ethnic background. In addition, the C3orf21 gene may be a potential susceptibility marker for lung adenocarcinoma independent of ethnic background and environmental agents.

Discovery of a highly potent series of oxazole-based phosphodiesterase 4 inhibitors.

Substituted quinolyl oxazoles were discovered as a novel and highly potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationship studies revealed that the oxazole core, with 4-carboxamide and 5-aminomethyl groups, is a novel PDE4 inhibitory pharmacophore. Selectivity profiles and in vivo biological activity are also reported.

Cyclic urea derivatives as potent NK1 selective antagonists. Part II: Effects of fluoro and benzylic methyl substitutions.

A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.

Cyclic urea derivatives as potent NK1 selective antagonists.

A series of novel five- and six-membered ring urea derivatives have been described as potent and selective NK1 receptor antagonists. Several compounds in this series exhibited good oral activity and brain penetration. Syntheses of these compounds are also described herein.