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Journal Article

Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bioware; Cell Death; Cell Line, Tumor; Cell Proliferation; Cyclohexanecarboxylic Acids; HeLa-luc; Humans; Inhibitory Concentration 50; Mice; Mitosis; Protein kinase inhibitors; Protein-Serine-Threonine Kinases; Rats; Taxoids; Thiazoles; Xenograft Model Antitumor Assays

Aurora-A kinase is a one of the key regulators during mitosis progression. Aurora-A kinase is a potential target for anticancer therapies because overexpression of Aurora-A, which is frequently observed in some human cancers, results in aberrant mitosis leading to chromosomal instability and possibly tumorigenesis. MK-5108 is a novel small molecule with potent inhibitory activity against Aurora-A kinase. Although most of the Aurora-kinase inhibitors target both Aurora-A and Aurora-B, MK-5108 specifically inhibited Aurora-A kinase in a panel of protein kinase assays. Inhibition of Aurora-A by MK-5108 in cultured cells induced cell cycle arrest at the G(2)-M phase in flow cytometry analysis. The effect was confirmed by the accumulation of cells with expression of phosphorylated Histone H3 and inhibition of Aurora-A autophosphorylation by immunostaining assays. MK-5108 also induced phosphorylated Histone H3 in skin and xenograft tumor tissues in a nude rat xenograft model. MK-5108 inhibited growth of human tumor cell lines in culture and in different xenograft models. Furthermore, the combination of MK-5108 and docetaxel showed enhanced antitumor activities compared with control and docetaxel alone-treated animals without exacerbating the adverse effects of docetaxel. MK-5108 is currently tested in clinical trials and offers a new therapeutic approach to combat human cancers as a single agent or in combination with existing taxane therapies.

Journal Article

Animals; Apoptosis; B16-F10-luc-G5 cells; Bioware; Blotting, Western; Cell Line, Tumor; Escherichia coli; Female; Flow Cytometry; Gene Therapy; Genetic Vectors; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; NCI-H460-luc2; Neoplasms; Polymerase Chain Reaction; Survival Rate; TNF-Related Apoptosis-Inducing Ligand

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent inducer of tumor cell apoptosis, but concerns of considerable liver toxicity limit its uses in human cancer therapy. Here, we show that i.v. injected Escherichia coli DH5alpha (E. coli DH5alpha) specifically replicates in solid tumors and metastases in live animals. E. coli DH5alpha does not enter tumor cells and suits for being the vector for soluble TRAIL (sTRAIL), which induces apoptosis by activating cell-surface death receptors. With the high 'tumor-targeting' nature, we demonstrate that intratumoral (i.t.) and intravenous injection of sTRAIL-expressing E. coli DH5alpha results in the tumor-targeted release of biologically active molecules, which leads to a dramatic reduction in the tumor growth rate and the prolonged survival of tumor-bearing mice. TRAIL delivery by E. coli DH5alpha did not cause any detectable toxicity to any organs, suggesting that E. coli DH5alpha-delivered sTRAIL protein therapy may provide a feasible and effective form of treatment for solid tumors.

Journal Article

Animals; Bioware; Carbon; Carrier Proteins; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Electron Transport Complex I; Gene Knockdown Techniques; Humans; Mass Spectrometry; MDA-MB-231-D3H2LN cells; Mice; Mitochondria; Mitochondrial Proteins; Neoplasm Metastasis; Neoplasms; Oxidative Phosphorylation; Protein Biosynthesis; Protein Stability; Rotenone

p32/gC1qR/C1QBP/HABP1 is a mitochondrial/cell surface protein overexpressed in certain cancer cells. Here we show that knocking down p32 expression in human cancer cells strongly shifts their metabolism from oxidative phosphorylation (OXPHOS) to glycolysis. The p32 knockdown cells exhibited reduced synthesis of the mitochondrial-DNA-encoded OXPHOS polypeptides and were less tumorigenic in vivo. Expression of exogenous p32 in the knockdown cells restored the wild-type cellular phenotype and tumorigenicity. Increased glucose consumption and lactate production, known as the Warburg effect, are almost universal hallmarks of solid tumors and are thought to favor tumor growth. However, here we show that a protein regularly overexpressed in some cancers is capable of promoting OXPHOS. Our results indicate that high levels of glycolysis, in the absence of adequate OXPHOS, may not be as beneficial for tumor growth as generally thought and suggest that tumor cells use p32 to regulate the balance between OXPHOS and glycolysis.

Journal Article

Xen14, Xen 14, E. coli Xen14, IVIS, Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides/chemical synthesis/*pharmacology; Bacterial Infections/*metabolism/microbiology/prevention & control; Cell Line; Cells, Cultured; Chemokine CCL2/metabolism; Chemokine CCL7/metabolism; Chemokine CXCL1/metabolism; Chemokines/*metabolism; Female; Humans; Interleukin-8/metabolism; Leukocytes/cytology/*metabolism; Leukocytes, Mononuclear/cytology/drug effects/metabolism; Macrophages/cytology/drug effects/metabolism; Mice; Mice, Inbred C57BL; Molecular Sequence Data; NF-kappa B/metabolism; Phosphatidylinositol 3-Kinases/metabolism; Phosphorylation/drug effects; Staphylococcal Infections/microbiology/prevention & control; Staphylococcus aureus/drug effects; p38 Mitogen-Activated Protein Kinases/metabolism

With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-kappaB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.

Journal Article

Animals; Antineoplastic Agents; Apoptosis; Bioware; Caspase 3; Cell Line, Tumor; Chemokines, CC; Disease Progression; Enzyme Activation; Etoposide; Humans; Male; Mice; Mice, Nude; PC-3M-luc; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Receptors, CCR; Signal Transduction

Despite recent advances in treatment and management of prostate cancer (PCa), it remains the second leading cause of cancer-related deaths among men in the US. Chemotherapy is one of the treatment alternatives for hormone refractory metastatic PCa. However, current chemotherapeutic regimens provide palliative benefit but relatively modest survival advantage primarily due to chemo-resistance and upregulated antiapoptotic machineries in PCa cells. Therefore, blocking the mechanisms responsible for suppression of apoptosis might improve current chemotherapeutic regimens. In this study, we show that CC chemokine receptor-9 (CCR9) and its natural ligand CCL25 interaction upregulates antiapoptotic proteins (i.e., PI3K, AKT, ERK1/2 and GSK-3beta) and downregulate activation of caspase-3 in PCa cells. Significant downregulation of these CCR9-mediated antiapoptotic proteins in the presence of a PI3K inhibitor (wortmannin), further suggests that the antiapoptotic action of CCR9 is primarily regulated through PI3K. Furthermore, the cytotoxic effect of etoposide was significantly inhibited in the presence of CCL25, and this inhibitory effect of CCL25 was abrogated when CCR9-CCL25 interaction was blocked using anti-CCR9 monoclonal antibodies. In conformation to these in vitro studies, significant reduction in tumor burden was found in mice receiving CCL25 neutralizing antibodies and etoposide together as compared to both as a single agent. These results suggest that the CCR9-CCL25 axis mediates PI3K/AKT-dependent antiapoptotic signals in PCa cells and could be a possible reason for low apoptosis and modest chemotherapeutic response. Therefore, targeting CCR9-CCL25 axis with cytotoxic agents may provide better therapeutic outcomes than using cytotoxic agents alone.