Citation Details

Journal Article

Animals; Apoptosis; Benzoxazines; Bioware; Breast Neoplasms; Cannabinoids; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Cyclooxygenase 2; Dinoprostone; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Mammary Neoplasms, Experimental; MDA-MB-231-D3H2LN cells; Mice; Mice, Inbred C3H; Mice, SCID; Mice, Transgenic; Microscopy, Confocal; Morpholines; Naphthalenes; Neoplasm Metastasis; Neovascularization, Pathologic; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; RNA, Small Interfering; Signal Transduction; Transfection; Xenograft Model Antitumor Assays

Cannabinoids have been reported to possess antitumorogenic activity. Not much is known, however, about the effects and mechanism of action of synthetic nonpsychotic cannabinoids on breast cancer growth and metastasis. We have shown that the cannabinoid receptors CB1 and CB2 are overexpressed in primary human breast tumors compared with normal breast tissue. We have also observed that the breast cancer cell lines MDA-MB231, MDA-MB231-luc, and MDA-MB468 express CB1 and CB2 receptors. Furthermore, we have shown that the CB2 synthetic agonist JWH-133 and the CB1 and CB2 agonist WIN-55,212-2 inhibit cell proliferation and migration under in vitro conditions. These results were confirmed in vivo in various mouse model systems. Mice treated with JWH-133 or WIN-55,212-2 showed a 40% to 50% reduction in tumor growth and a 65% to 80% reduction in lung metastasis. These effects were reversed by CB1 and CB2 antagonists AM 251 and SR144528, respectively, suggesting involvement of CB1 and CB2 receptors. In addition, the CB2 agonist JWH-133 was shown to delay and reduce mammary gland tumors in the polyoma middle T oncoprotein (PyMT) transgenic mouse model system. Upon further elucidation, we observed that JWH-133 and WIN-55,212-2 mediate the breast tumor-suppressive effects via a coordinated regulation of cyclooxygenase-2/prostaglandin E2 signaling pathways and induction of apoptosis. These results indicate that CB1 and CB2 receptors could be used to develop novel therapeutic strategies against breast cancer growth and metastasis.

Journal Article

Actins; Animals; B16-F10-luc-G5; Bioware; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cofilin 1; Cytoskeleton; Female; Humans; Immunoblotting; Immunoprecipitation; Male; Mammary Neoplasms, Experimental; MDA-MB-231-D3H2LN cells; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Protein Binding; Protein Kinases; Protein Phosphatase 2; Protein-Serine-Threonine Kinases; RNA Interference; Transplantation, Heterologous

Metastasis leads to the death of most cancer patients, and basal breast cancer is the most aggressive breast tumor type. Metastasis involves a complex cell migration process dependent on cytoskeletal remodeling such that targeting such remodeling in tumor cells could be clinically beneficial. Here we show that Hormonally Up-regulated Neu-associated Kinase (HUNK) is dramatically down-regulated in tumor samples and cell lines derived from basal breast cancers. Reconstitution of HUNK expression in basal breast cancer cell lines blocked actin polymerization and reduced cell motility, resulting in decreased metastases in two in vivo murine cancer models. Mechanistically, HUNK overexpression sustained the constitutive phosphorylation and inactivation of cofilin-1 (CFL-1), thereby blocking the incorporation of new actin monomers into actin filaments. HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A), a phosphatase putatively acting on CFL-1, from binding to CFL-1. Our investigation of HUNK suggests that the interaction between PP2A and CFL-1 may be a target for antimetastasis therapy, particularly for basal breast cancers.

Journal Article

Xen31, Xen 31, MRSA, S. aureus, IVIS, Bioluminescence, Animals; Bacterial Infections/*drug therapy; Burns/drug therapy/microbiology; Candida/drug effects; Cations; Gram-Negative Bacteria/drug effects; Gram-Positive Bacteria/drug effects; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; *Photochemotherapy; Photosensitizing Agents/*chemical synthesis/chemistry/pharmacology; Porphyrins/*chemical synthesis/chemistry/pharmacology; Solubility; Staphylococcal Infections/drug therapy/microbiology; Structure-Activity Relationship

Structures of typical photosensitizers used in antimicrobial photodynamic therapy are based on porphyrins, phthalocyanines, and phenothiazinium salts, with cationic charges at physiological pH values. However, derivatives of the porphycene macrocycle (a structural isomer of porphyrin) have barely been investigated as antimicrobial agents. Therefore, we report the synthesis of the first tricationic water-soluble porphycene and its basic photochemical properties. We successfully tested it for in vitro photoinactivation of different Gram-positive and Gram-negative bacteria, as well as a fungal species (Candida) in a drug-dose and light-dose dependent manner. We also used the cationic porphycene in vivo to treat an infection model comprising mouse third degree burns infected with a bioluminescent methicillin-resistant Staphylococcus aureus strain. There was a 2.6-log(10) reduction (p < 0.001) of the bacterial bioluminescence for the PDT-treated group after irradiation with 180 J.cm(-2) of red light.

Journal Article

Ovarian cancer; Molecular imaging; Intraoperative imaging; Fluorescence imaging

OBJECTIVES: Cytoreductive surgery is a cornerstone of therapy in metastatic ovarian cancer. While conventional white light (WL) inspection detects many obvious tumor foci, careful histologic comparison has shown considerable miss rates for smaller foci. The goal of this study was to compare tumor detection using WL versus near infrared (NIR) imaging with a protease activatable probe, as well as to evaluate the ability to quantify NIR fluorescence using a novel quantitative optical imaging system.

METHODS: A murine model for peritoneal carcinomatosis was generated and metastatic foci were imaged using WL and NIR imaging following the i.v. administration of the protease activatable probe ProSense750. The presence of tumor was confirmed by histology. Additionally, the ability to account for variations in fluorescence signal intensity due to changes in distance between the catheter and target lesion during laparoscopic procedures was evaluated.

RESULTS: NIR imaging with a ProSense750 significantly improved upon the target-to-background ratios (TBRs) of tumor foci in comparison to WL imaging (minimum improvement was approximately 3.5 fold). Based on 52 histologically validated samples, the sensitivity for WL imaging was 69%, while the sensitivity for NIR imaging was 100%. The effects of intraoperative distance changes upon fluorescence intensity were corrected in realtime, resulting in a decrease from 89% to 5% in signal variance during fluorescence laparoscopy.

CONCLUSIONS: With its molecular specificity, low background autofluorescence, high TBRs, and quantitative signal, optical imaging with NIR protease activatable probes greatly improves upon the intraoperative detection of ovarian cancer metastases.

Journal Article

Amino Acid Sequence; Animals; Bioware; Brucella melitensis; Brucellosis; Disease Models, Animal; Flagella; Gene Deletion; Gene Expression Regulation, Bacterial; Interferon Regulatory Factor-1; Macrophages; Mice; Mice, Mutant Strains; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; pXen-13; Quorum Sensing; Repressor Proteins; Trans-Activators; Virulence Factors

Brucella melitensis is an intracellular pathogen that establishes a replicative niche within macrophages. While the intracellular lifestyle of Brucella is poorly understood and few virulence factors have been identified, components of a quorum-sensing pathway in Brucella have recently been identified. The LuxR-type regulatory protein, VjbR, and an N-acylhomoserine lactone signaling molecule are both involved in regulating expression of the virB-encoded type IV secretion system. We have identified a second LuxR-type regulatory protein (BlxR) in Brucella. Microarray analysis of a blxR mutant suggests that BlxR regulates the expression of a number of genes, including those encoding the type IV secretion system and flagella. Confirming these results, deletion of blxR in B. melitensis reduced the transcriptional activities of promoters for the virB operon, flagellar genes, and another putative virulence factor gene, bopA. Furthermore, our data suggested that both BlxR and VjbR are positively autoregulated and cross-regulate the expression of each other. The blxR deletion strain exhibited reduced growth in macrophages, similar to that observed for a vjbR deletion strain. However, unlike the vjbR deletion, the blxR deletion did not fully attenuate virulence in mice. More strikingly, bioluminescent imaging revealed that dissemination of the blxR mutant was similar to that of wild-type B. melitensis, while the vjbR mutant was defective for systemic spread in IRF-1(-/-) mice, suggesting that these regulators are not functionally redundant but that they converge in a common pathway regulating bacterial processes.