Current Signal Transduction Therapy - Volume 9, Issue 1, 2014

Aims: We investigated whether bortezomib synergizes with arsenious acid in killing promyelocytic leukemia HL-60 cells in vitro and in vivo. Main Methods: Cell culture, MTT assay, Hoechest 33324 staining, flow cytometry assay, determination of DNA fragmentation, immunoblotting analysis, HL60 xenograft mice models and animal experiments. Key Findings: Bortezomib inhibited proliferation of HL-60 cells in a time- and dose-dependent manner. 20nM bortezomib enhanced the cytotoxic effect of arsenious acid. Consistent with the results in vitro, bortezomib or arsenious acid alone exhibited antitumor activity in HL-60 cell-xenografted mice, whereas combined bortezomib and arsenious acid treatment showed a greater antitumor activity than single treatment. The mice tolerated the drugs with no obvious side-effects. Further mechanistic study found that bortezomib induced cell apoptosis associated with activation of the caspase cascade, including down-regulation of Bcl-2 and cleavage of caspase family members and PARP. Significance: These results demonstrate that the combination of bortezomib and arsenious acid could be more effective than single agent in inhibiting HL-60 cells viability.

Background: Glioblastoma is the most aggressive and common primary tumor of the central nervous system. Resistance to temozolomide, the first-line chemotherapy for glioblastoma, always leads to treatment failure. Further understanding of the molecular mechanisms of temozolomide resistance in glioblastoma is desperately needed. The purpose of this study was to identify miRNAs correlated with temozolomide treatment in glioblastoma paitents. Methods: miRNA expression microarray data of 82 glioblastoma samples were obtained from the Chinese Glioma Genome Atlas database (http://www.cgga.org.cn). In order to identify miRNAs correlated with temozolomide reponse, the significance of the association between each miRNA expression and overall survival of temozolomide treated glioblastoma patients was analyzed by univariate Cox proportional hazard regression analysis. Gene expression profile associated with miR-629-3p was determined using whole genome mRNA expression microarray data. Subsequently, biological progresses related to the miR-629-3p associated gene expression profile were identified by gene ontology analysis Results: The miR629-3p level was significantly correlated with overall survival in patients who underwent temozolomide chemotherapy, while a higher miR629-3p level failed to improve overall survival in patients who had not received temozolomide treatment. Gene ontology analysis showed that miR-629-3p associated genes were involved in the biological processes including translation, translational elongation, and ribonucleoprotein complex biogenesis. Conclusion: High-level miR629-3p expression was associated with prolonged overall survival in patients who underwent temozolomide chemotherapy, indicating that miR-629-3p may be a predictive biomarker for temozolomide response, a guide for clinical treatment decisions, and a target for glioblastoma therapy.

Growth factor signaling via receptor tyrosine kinases plays a central role in initiating and maintaining a malignant phenotype. Fibroblast growth factors (FGF) and their receptor family (FGFR1-4) are key players in various human solid and hematological tumors and have been linked to tumor cell proliferation, resistance to chemotherapy and apoptosis, angiogenesis, invasion and metastasis. FGFRs are commonly activated by genomic alterations or mutations and various approaches to targeted inhibition have been developed. The deeper understanding of the underlying signal transduction mechanisms has generated novel targeted therapy approaches like ligand-traps, receptor-specific antibodies or small molecule kinase inhibitors that are currently undergoing preclinical and clinical development for the treatment of human cancers.

Pancreatic cancer is one of the most common human cancers with very low survival rate. So far, the difficulties to make early diagnosis and find curative therapy for this malignant disease remain challenging. Considering Chinese medicine with a long history of clinical application in treating various human diseases, it has been now introduced into the anti-cancer treatment and begun to attract attentions of researchers worldwide. Here, we summarize the recent studies on the anti-tumor activity of Chinese medicine in human pancreatic cancer and the potential molecular mechanisms.

Pioneer works have identified some microRNAs (miRNAs) with oncogenic or tumor-suppressive properties in glioblastoma multiforme (GBM), an aggressive brain tumor with dismal prognosis. Differential expression of these noncoding small RNA in cancers positions them as attractive biomarkers for diagnosis, prognosis and therapeutic decision in GBMs. In addition, abnormal miRNAs provide new interesting therapeutic targets for clinical GBM treatments despite the hurdles associated with such an approach. This review firstly summarizes abnormal expressed genes and upstream miRNAs in GBMs. Next, our focus will be towards the signature of miRNAs in GBM, and discuss the importance of circulating miRNAs for cancer diagnosis. Finally, we summarize present miRNA target therapeutic strategies, and discuss the deficiencies and challenges.

Stem cells, which maintain self-renewal behavior and produce multiple mature cells, are recognized to be the best cell source for transplantation in regenerative medicine. Recently, stem-cell based transplantation has become an important pre-clinical attempt for neuronal injury and degeneration diseases, such as spinal cord injury, amyotrophic lateral sclerosis, and Alzheimer disease. However, the poor survival rate of stem cells and only a limited number of induced neurons from the cells were found in pre-clinical trials. Therefore, it is necessary to develop a rational procedure for stem cells transplantation. This review summarizes recent promising progress in the investigation of stem cell and biomaterials, and hypothesizes a useful transplant approach for stem cell therapy in neuronal diseases.

We analyzed the clinicopathological characteristics of 1,425 primary breast cancer patients admitted to the Cancer Hospital of Shantou University Medical College from 1995 to 2008. The peak age group was 45-49 years old and median age was 49 years old. Sixty-two percent of the patients were pre-menopausal, while the remaining was postmenopausal. In the present study, 53% of the patients were in stage I-II of TNM staging. Immunohistochemical detection demonstrated that estrogen receptor (ER), progestrone receptor (PR) and human epidermal growth factor receptor 2 (Her-2) were 59%, 56% and 32% positive, respectively. The most common histological type was invasive ductal carcinoma accounting for 76% of total patients. Most patients received surgical treatment (97.2%) and chemotherapy (74.4%). The overall five-year and ten-year survival rates were 63% and 56% respectively. Multivariate analyses revealed that the tumor size, axillary lymph node involvement, and clinical staging were independent risk factors for overall survival (OS). In summary, the largest cohort of breast cancer patients in Eastern Guangdong was analyzed with their clinicopathological characteristics. We demonstrated that the similar clinical outcomes were obtained by multi-modality therapy, and the tumor size and lymph node involvement are the independent prognostic factors being same as the previous reports.

7-Difluoromethyl-5, 4’-dimethoxygenistein (DFMG), prepared by the difluoromethylation and alkylation of Genistein, is a new active chemical entity. In this study, we investigated the inhibitory effect of DFMG on Lysophosphatidyl choline (LPC)-induced apoptosis of human umbilical vein endothelial cells-12 (HUVEC-12) through mitochondrial apoptosis pathway. Lysophosphatidyl choline (LPC) was used to build apoptosis model in HUVEC-12 cells. The apoptosis rate in each group was determined by using flow cytometry of ANNEXIN V/PI staining. The mean ffluorescence intensity (MFI) of mitochondria mmembrane ppotential (MMP) was determined by using flow cytometry. The expression levels of cytochrome C (CytC), p-JNK and PARP were detected by performing western blotting assay. The activities of caspase-3 and caspase-9 were detected by a colorimetric method with caspase colorimetric assay kits. As compared with the control group, DFMG notably decreased the apoptosis rate, the MFI of the MMP, and the generation of Reactive Oxygen Species (ROS) induced by LPC. In addition, DFMG had suppressive effects on the expressions of CytC, P-JNK, and PARP, as well as on the activities of caspase-3 and caspase-9 in LPC-treated HUVEC-12 cells. DFMG can antagonize LPC-induced apoptosis of HUVE-12 cells. The underlying mechanism may be involved in the inhibition of mitochondrial apoptosis pathway.