Cancer Science & Therapy

Despite being the leading cause of cancer death, targeted therapy for gastric cancer is yet to be established. Wnt/β-catenin signaling is highly deregulated in cancers of gastrointestinal origin including gastric cancers. Stabilization and deregulation of β-catenin occurs at multiple levels and so is being needed to identify a spectrum of Wnt inhibitors to combat deregulated Wnt signaling at the level of various targets and also in different combinations. We developed a luciferase reporter based gastric cancer cellular assay system for Wnt pathway modulator screening and identified nimesulide, a known COX-2 inhibitor as an inhibitor of Wnt/β catenin signaling pathway. Comprehensive signaling pathway profiling revealed that nimesulide could inhibit STAT3, IRF1 and RXR signaling apart from inhibiting Wnt/β-catenin-Myc-E2F signaling cascade. Nimesulide elicits a strong anti-proliferative effect by promoting cell cycle arrest in multiple gastric cancer cell lines. Inhibition of Wnt and STAT3 signaling are found to be COX-2 independent, while the inhibition of RXR and IRF1 pathways are due to the COX-2 inhibiting feature of nimesulide. While nimesulide is capable of activating Notch signaling in gastric cancer cells, celecoxib inhibits Wnt, Myc, E2F, RXR, STAT3, MAPK and Notch signaling pathways in gastric cancer cells. Signaling pathway focused analysis of gastric cancer transcriptome revealed that Wnt, STAT3, IRF1 and RXR signaling pathway are highly deregulated in majority of gastric tumors and indicates the potential of nimesulide and celecoxib class of drugs for targeted gastric cancer therapeutics. The differential inhibition of multiple signaling by nimesulide and celecoxib deserve further investigation.

Etoposide is well-known drug long been used in clinical trials for treating various cancers. The beneficial action of drug can be used in treatment of small cell and non-small cell lung cancer, lymphoma and ovarian cancer. In this study we examined the effect of etoposide on morphological structure of renal tissue. Studies showed that long-term treatment of etoposide given at dose of 1 mg/kg i.p for period of 8 weeks resulted in histological changes that are associated with dilated proximal convoluted tubules (PCT) with enlarged lumen (L) and vacuolation in their epithelium around nucleus. The onset of necrosis and atrophied glomerulus is also observed. Additionally, ultrastructural studies showed presence of mitochondria in segments and lumen with broken microvilli. Furthermore, biochemical finding’s in etoposide treated kidney displayed significant increase in Glutathione-STransferase (GST), Glutathione Peroxidase (Gpx) and decrease in glutathione reductase (GR), gamma glutamyl transpeptidase (GGT) activities however, glutathione (GSH), Catalase (CAT) and Lipid peroxidation (MDA Content) showed non-significant decrease. The drug metabolizing enzyme’s Cytochrome p450 (Cyp450) showed no change whereas, Cytochrome b5 (Cyp b5) showed significant decrease. Thus we conclude that etoposide does not cause nephrotoxic effect at given dose level.

There is emerging and convincing data that certain cells, administered systemically, have a natural propensity to migrate to cancerous tissues in preclinical models. Examples of such cells include neural stem cells, bone marrow mesenchymal stem cells, umbilical cord Wharton’s jelly stem cells [3], and defensive cells.This homing ability can be exploited by using cells as stealth vehicles to ferry therapeutic nanomaterials to tumors to facilitate penetration, reduce potential toxicity, reduce potential unwanted immune consequences, and reduce removal by the reticuloendothelial system (RES).

Background: One of the major epigenetic changes in human cancer is DNA methylation of tumour suppressor genes which leads to silencing of gene leading to disease progression. Therefore, DNA methylation status of such genes may serve as the epigenetic biomarker for prognosis of human Chronic Myeloid Leukemia. Material and methods: We used MSP-PCR technique for the analysis of aberrant promoter DAPK1 methylation on 200 CML venous blood samples. Stastical analysis was done for evaluating differences between different parameters using SPSS 16.0 version. Results: We could detect 91/200 promoter methylation (45.5%) in CML patients. Percentage of methylation detected was seen higher in blast phase (63.07%) and in accelerated phase (48.1%) than in chronic phase (29.6%). A significant correlation was seen between CML stages and DAPK1 aberrant methylation. We also found a significant association of DAPK1 methylation in gender and in haematological resistance CML patients. However no correlation was found between DAPK1 promoter methylation and other clinical parameters like age, BCR-ABL type and Thrombocytopenia. Conclusion: In summary we concluded that methylation status of DAPK1 gene is associated with advanced phase of CML and may be related to disease progression in chronic myeloid leukemia. Further study on a more number of patients is needed to explore the role of DAPK1 methylation in the prognosis of CML.

Colon cancer is the third most common cause of cancer, and epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5-2 folds with obesity-associated colon cancer accounting for 14- 35% of total incidence. So far, solely leptin was found to promote the motility and invasion of carcinoma cells. Adiponectin is another prominent protein hormone secreted by differentiated adipocytes. However, the effect of adiponectin on migration of carcinoma cells is mostly unknown. In this study, we found that adiponectin significantly increased the locomotion of human SW480 colon carcinoma cells. This pro-migratory effect is mediated by an activation of an autocrine loop of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), as was shown by neutralizing antibodies. Treatment of the cells with these specific antibodies completely abrogated the adiponectin-promoted locomotion. The intracellular signal transduction underlying this effect involves the activity of the transcription factors Stat-3 and nuclear factor-kappa B (NFκB), but also the activation of the phosphatidylinositol- 3-kinase/Akt pathway, as proven by the use of specific inhibitors. Blockade of NFκB activation abolished the pro-migratory effect of adiponectin by inhibiting the secretion of IL-8 and MCP-1. Here, we report on a new biological function of adiponectin in the regulation of colon cancer progression by stimulating tumor cell migration via an autocrine IL-8 and MCP-1 loop. Thus our findings have potential clinical implications, because understanding the impact of adiponectin on tumor cell migration and the underlying signal transduction mechanisms is mandatory for future development of novel therapeutics to treat obesity-associated colorectal cancer.