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1.  The effect of gartanin, a naturally- occurring xanthone in mangosteen juice, on the mTOR pathway, autophagy, apoptosis and the growth of human urinary bladder cancer cell Lines 
Nutrition and cancer  2013;65(0 1):68-77.
Garcinia mangostana, often referred to as “mangosteen,” is a fruit grown in Southeast Asia, and has been used for centuries as a local beverage and natural medicine. Its bioactive compounds, xanthones (i.e. gartanin, α-mangostin, etc), have reported effects on ailments ranging from skin infections and inflammation, to urinary tract infections. We demonstrate that mangosteen xanthones (i.e. gartanin and α-mangostin) at pharmacologically achievable concentrations inhibit the growth of cancer cell lines from different stages of human urinary bladder cancer. The growth inhibitory effects of gartanin in mouse embryonic fibroblasts (MEFs) are at least in part dependent on the existence of p53 or TSC1. Indeed, further studies have shown that gartanin treatment of bladder cancer cell lines T24 and RT4 resulted in a marked suppression of p70S6 and 4E-BP1 expression and induction of autophagy, suggesting the inhibition of the mTOR pathway. In addition, gartanin down-regulated the expression of Bcl-2 and activated the p53 pathway leading to apoptosis induction. Together, these results suggested that gartanin is a multiple targeting agent that is suitable for further study into its chemopreventive properties for human urinary bladder cancer.
PMCID: PMC3671488  PMID: 23682785
Gartanin; human urinary bladder cancer; the mTOR pathway; autophagy
2.  Anti-leukemia activity of a bacterial toxin with natural specificity for LFA-1 on white blood cells 
Leukemia research  2009;34(6):777-785.
The oral bacterium, Aggregatibacter actinomycetemcomitans, produces a leukotoxin (LtxA) that is specific for white blood cells (WBCs) from humans and Old World primates by interacting with lymphocyte function antigen-1 (LFA-1) on susceptible cells. To determine if LtxA could be used as a therapeutic agent for the treatment of WBC diseases, we tested the in vitro and in vivo anti-leukemia activity of the toxin. LtxA kills human malignant WBC lines and primary leukemia cells from acute myeloid leukemia patients, but healthy peripheral blood mononuclear cells (PBMCs) are relatively resistant to LtxA-mediated cytotoxicity. Levels of LFA-1 on cell lines correlated with killing by LtxA and the toxin preferentially killed cells expressing the activated form of LFA-1. In a SCID mouse model for human leukemia, LtxA had potent therapeutic value resulting in long-term survival in LtxA-treated mice. Intravenous infusion of LtxA into a rhesus macaque resulted in a drop in WBC counts at early times post-infusion; however, red blood cells, platelets, hemoglobin and blood chemistry values remained unaffected. Thus, LtxA may be an effective and safe novel therapeutic agent for the treatment of hematologic malignancies.
PMCID: PMC2859097  PMID: 19747730
Acute myeloid leukemia; lymphoma; immunotoxin; targeted therapy
3.  Gangliosides Block Aggregatibacter Actinomycetemcomitans Leukotoxin (LtxA)-Mediated Hemolysis  
Toxins  2010;2(12):2824-2836.
Aggregatibacter actinomycetemcomitans is an oral pathogen and etiologic agent of localized aggressive periodontitis. The bacterium is also a cardiovascular pathogen causing infective endocarditis. A. actinomycetemcomitans produces leukotoxin (LtxA), an important virulence factor that targets white blood cells (WBCs) and plays a role in immune evasion during disease. The functional receptor for LtxA on WBCs is leukocyte function antigen-1 (LFA-1), a β-2 integrin that is modified with N-linked carbohydrates. Interaction between toxin and receptor leads to cell death. We recently discovered that LtxA can also lyse red blood cells (RBCs) and hemolysis may be important for pathogenesis of A. actinomycetemcomitans. In this study, we further investigated how LtxA might recognize and lyse RBCs. We found that, in contrast to a related toxin, E. coli α-hemolysin, LtxA does not recognize glycophorin on RBCs. However, gangliosides were able to completely block LtxA-mediated hemolysis. Furthermore, LtxA did not show a preference for any individual ganglioside. LtxA also bound to ganglioside-rich C6 rat glioma cells, but did not kill them. Interaction between LtxA and C6 cells could be blocked by gangliosides with no apparent specificity. Gangliosides were only partially effective at preventing LtxA-mediated cytotoxicity of WBCs, and the effect was only observed when a high ratio of ganglioside:LtxA was used over a short incubation period. Based on the results presented here, we suggest that because of the similarity between N-linked sugars on LFA-1 and the structures of gangliosides, LtxA may have acquired the ability to lyse RBCs.
PMCID: PMC3153184  PMID: 22069577
erythrocytes; toxin; periodontal disease; endocarditis; RTX toxin
4.  Both Leukotoxin and Poly-N-Acetylglucosamine Surface Polysaccharide Protect Aggregatibacter actinomycetemcomitans Cells from Macrophage Killing 
Microbial pathogenesis  2008;45(3):173-180.
Two virulence factors produced by the periodontopathogen Aggregatibacter actinomycetemcomitans are leukotoxin, a secreted lipoprotein that kills human polymorphonuclear leukocytes and macrophages, and poly-N-acetylglucosamine (PGA), a surface polysaccharide that mediates intercellular adhesion, biofilm formation and detergent resistance. In this study we examined the roles of leukotoxin and PGA in protecting A. actinomycetemcomitans cells from killing by the human macrophage cell line THP-1. Monolayers of THP-1 cells were infected with single-cell suspensions of a wild-type A. actinomycetemcomitans strain, or of isogenic leukotoxin or PGA mutant strains. After 48 h, viable bacteria were enumerated by dilution plating, macrophage morphology was evaluated microscopically, and macrophage viability was measured by a Trypan blue dye exclusion assay. The number of A. actinomycetemcomitans CFUs increased approximately 2-fold in wells infected with the wild-type strain, but decreased by approximately 70–90% in wells infected with the leukotoxin and PGA mutant strains. Infection with the wild-type or leukotoxin mutant strain caused a significant decrease in THP-1 cell viability, whereas infection with the PGA mutant strain did not result in any detectable changes in THP-1 viability. Pre-treatment of wild-type A. actinomycetemcomitans cells with the PGA-hydrolyzing enzyme dispersin B rendered them sensitive to killing by THP-1 cells. We concluded that both leukotoxin and PGA are necessary for evasion of macrophage killing by A. actinomycetemcomitans.
PMCID: PMC2586082  PMID: 18573331
Aggregatibacter actinomycetemcomitans; biofilm; dispersin B; HL-60; J774-1; leukotoxin; macrophage; poly-N-acetylglucosamine; THP-1

Results 1-4 (4)