Molecular interaction of a kinase inhibitor midostaurin with anticancer drug targets, S100A8 and EGFR: transcriptional profiling and molecular docking study for kidney cancer therapeutics.

The S100A8 and epidermal growth factor receptor (EGFR) proteins are proto-oncogenes that are strongly expressed in a number of cancer types. EGFR promotes cellular proliferation, differentiation, migration and survival by activating molecular pathways. Involvement of proinflammatory S100A8 in tumor cell differentiation and progression is largely unclear and not studied in kidney cancer (KC). S100A8 and EGFR are potential therapeutic biomarkers and anticancer drug targets for KC. In this study, we explored molecular mechanisms of interaction profiles of both molecules with potential anticancer drugs. We undertook transcriptional profiling in Saudi KCs using Affymetrix HuGene 1.0 ST arrays. We identified 1478 significantly expressed genes, including S100A8 and EGFR overexpression, using cut-off p value <0.05 and fold change ≥2. Additionally, we compared and confirmed our findings with expression data available at NCBI's GEO database. A significant number of genes associated with cancer showed involvement in cell cycle progression, DNA repair, tumor morphology, tissue development, and cell survival. Atherosclerosis signaling, leukocyte extravasation signaling, notch signaling, and IL-12 signaling were the most significantly disrupted signaling pathways. The present study provides an initial transcriptional profiling of Saudi KC patients. Our analysis suggests distinct transcriptomic signatures and pathways underlying molecular mechanisms of KC progression. Molecular docking analysis revealed that the kinase inhibitor "midostaurin" has amongst the selected drug targets, the best ligand properties to S100A8 and EGFR, with the implication that its binding inhibits downstream signaling in KC. This is the first structure-based docking study for the selected protein targets and anticancer drug, and the results indicate S100A8 and EGFR as attractive anticancer targets and midostaurin with effective drug properties for therapeutic intervention in KC.

Potential mechanisms of hepatitis B virus induced liver injury.

Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury.

Impact of S100A8 expression on kidney cancer progression and molecular docking studies for kidney cancer therapeutics.

BACKGROUND/AIM: The proinflammatory protein S100A8, which is expressed in myeloid cells under physiological conditions, is strongly expressed in human cancer tissues. Its role in tumor cell differentiation and tumor progression is largely unclear and virtually unstudied in kidney cancer. In the present study, we investigated whether S100A8 could be a potential anticancer drug target and therapeutic biomarker for kidney cancer, and the underlying molecular mechanisms by exploiting its interaction profile with drugs. MATERIALS AND METHODS: Microarray-based transcriptomics experiments using Affymetrix HuGene 1.0 ST arrays were applied to renal cell carcinoma specimens from Saudi patients for identification of significant genes associated with kidney cancer. In addition, we retrieved selected expression data from the National Center for Biotechnology Information Gene Expression Omnibus database for comparative analysis and confirmation of S100A8 expression. Ingenuity Pathway Analysis (IPA) was used to elucidate significant molecular networks and pathways associated with kidney cancer. The probable polar and non-polar interactions of possible S100A8 inhibitors (aspirin, celecoxib, dexamethasone and diclofenac) were examined by performing molecular docking and binding free energy calculations. Detailed analysis of bound structures and their binding free energies was carried out for S100A8, its known partner (S100A9), and S100A8-S100A9 complex (calprotectin). RESULTS: In our microarray experiments, we identified 1,335 significantly differentially expressed genes, including S100A8, in kidney cancer using a cut-off of p<0.05 and fold-change of 2. Functional analysis of kidney cancer-associated genes showed overexpression of genes involved in cell-cycle progression, DNA repair, cell death, tumor morphology and tissue development. Pathway analysis showed significant disruption of pathways of atherosclerosis signaling, liver X receptor/retinoid X receptor (LXR/RXR) activation, notch signaling, and interleukin-12 (IL-12) signaling. We identified S100A8 as a prospective biomarker for kidney cancer and in silico analysis showed that aspirin, celecoxib, dexamethasone and diclofenac binds to S100A8 and may inhibit downstream signaling in kidney cancer. CONCLUSION: The present study provides an initial overview of differentially expressed genes in kidney cancer of Saudi Arabian patients using whole-transcript, high-density expression arrays. Our analysis suggests distinct transcriptomic signatures, with significantly high levels of S100A8, and underlying molecular mechanisms contributing to kidney cancer progression. Our docking-based findings shed insight into S100A8 protein as an attractive anticancer target for therapeutic intervention in kidney cancer. To our knowledge, this is the first structure-based docking study for the selected protein targets using the chosen ligands.

Expression of matrix metalloproteinases (MMPs) in primary human breast cancer: MMP-9 as a potential biomarker for cancer invasion and metastasis.

BACKGROUND/AIM: Breast cancer (BC) is the most common type of cancer in Saudi women. Matrix metalloproteinases (MMPs) are endopeptidases with the ability to degrade extracellular matrix proteins. In healthy individual tissue disruption is prevented by precised regulation of MMPs; however, in cancer a number of MMPs are overexpressed causing tissue disruption and making tumor cells capable of invasion and metastasis. Invasive ductal carcinoma (IDC) of BCs are classified into grade 1 (G1), grade 2 (G2) and grade 3 (G3) tumors. MATERIALS AND METHODS: We performed a transcriptomic profiling of 38 surgically-resected breast tumors (4 G1, 17 G2 and 17 G3) using Affymetrix Gene 1.0 ST microarrays. Differentially expressed genes for each grade were identified by the Partek Genomic Suite 6.4 and expression analysis results were validated by immunohistochemistry at the protein level. Pathway analyses and establishment of clinical significance of findings were performed using the appropriate software. RESULTS: We identified 1,593 differentially expressed genes in BC grades in comparison to normal samples using a cut-off of p<0.05 and fold change >2. Out of these genes 429 were expressed throughout in all grades along with tumor progression while many others associated with specific grades (440 genes in G1, 203 in G2 and 394 in G3 only) were exclusively. Microarray results indicate that mRNA expression of MMP-1, -9,-11,-12, and -13 were up-regulated in higher BC grades when compared to normal breast tissues. MMP-9 was expressed in most IDC (97.5%) samples and was highly expressed in 55% of the tumors. Differential expression of MMP-9 significantly correlated with histological BC grades of (p=0.03) and strongly correlated with overall survival (p=0.08). CONCLUSION: Gene expression signatures are unique for specific grades. Overexpression of MMPs in higher grades might be associated with BC tumor invasion and metastasis. Therefore, MMPs, and MMP-9 in particular, are reliable candidates for diagnostic biomarker and drug target and further functional analyses have to be performed in order to confirm their role in BC. Our results also suggest the incidence of MMP-9 expression is high in IDC, but it is of limited prognostic value.

New anticancer agents: recent developments in tumor therapy.

Increasing recurrence of mammalian tumors and severe side-effects of chemotherapeutic agents reduce the clinical efficacy of a large variety of anticancer agents that are currently being used. Thus, there is always a constant need to develop alternative or synergistic anticancer drugs with minimal side-effects. One important strategy to develop effective anticancer agents is to study into anticancer agents derived from natural sources. Anticancer agents derived from plants and their derivatives have been proven to be effective for cancer prevention and therapeutics. Vinca alkaloid and their derivatives, alone and in combination with therapeutic agents, have been used for a long time for the treatment of various types of cancers. Polyphenols form one of the most important and extensively used classes of plant-derived therapeutics for cancer prevention or chemotherapy. The present review highlights a plethora of studies focused on the antineoplastic properties of plant-derived chemicals, such as Vinca alkaloid, saponins, and flavonoids.