1.Bioactive Dihydro-β-agarofuran Sesquiterpenoids from the Australian Rainforest Plant Maytenus bilocularis.
Wibowo M1, Levrier C1,2, Sadowski MC2, Nelson CC2, Wang Q3,4, Holst J3,4, Healy PC5, Hofmann A1,6, Davis RA1. J Nat Prod. 2016 Apr 27. [Epub ahead of print]
Chemical investigations of the CH2Cl2 extract obtained from the leaves of the Australian rainforest tree Maytenus bilocularis afforded three new dihydro-β-agarofurans, bilocularins A-C (1-3), and six known congeners, namely, celastrine A (4), 1α,6β,8α-triacetoxy-9α-benzoyloxydihydro-β-agarofuran (5), 1α,6β-diacetoxy-9α-benzoyloxy-8α-hydroxydihydro-β-agarofuran (6), Ejap-10 (11), 1α,6β-diacetoxy-9β-benzoyloxydihydro-β-agarofuran (12), and Ejap-2 (13). The major compound 1 was used in semisynthetic studies to afford four ester derivatives (7-10). The chemical structures of 1-3 were elucidated following analysis of 1D/2D NMR and MS data. The absolute configurations of bilocularins A (1) and B (2) were determined by single-crystal X-ray diffraction analysis. All compounds were evaluated for cytotoxic activity against the human prostate cancer cell line LNCaP; none of the compounds were active. However, several compounds showed similar potency to the drug efflux pump inhibitor verapamil in reversing the drug resistance of the human leukemia CEM/VCR R cell line.
2.Viral protein suppresses oxidative burst and salicylic acid-dependent autophagy and facilitates bacterial growth on virus-infected plants.
Zvereva AS1, Golyaev V1, Turco S1, Gubaeva EG1, Rajeswaran R1, Schepetilnikov MV2, Srour O2, Ryabova LA2, Boller T1, Pooggin MM1. New Phytol. 2016 Apr 27. doi: 10.1111/nph.13967. [Epub ahead of print]
Virus interactions with plant silencing and innate immunity pathways can potentially alter the susceptibility of virus-infected plants to secondary infections with nonviral pathogens. We found that Arabidopsis plants infected with Cauliflower mosaic virus (CaMV) or transgenic for CaMV silencing suppressor P6 exhibit increased susceptibility to Pseudomonas syringae pv. tomato (Pst) and allow robust growth of the Pst mutant hrcC-, which cannot deploy effectors to suppress innate immunity. The impaired antibacterial defense correlated with the suppressed oxidative burst, reduced accumulation of the defense hormone salicylic acid (SA) and diminished SA-dependent autophagy. The viral protein domain required for suppression of these plant defense responses is dispensable for silencing suppression but essential for binding and activation of the plant target-of-rapamycin (TOR) kinase which, in its active state, blocks cellular autophagy and promotes CaMV translation.
3.Mesothelin's minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane.
Su Y1,2, Tatzel K1, Wang X1, Belt B1, Binder P3, Kuroki L3, Powell MA3,4, Mutch DG3,4, Hawkins WG1,4, Spitzer D1,4. Oncotarget. 2016 Apr 22. doi: 10.18632/oncotarget.8925. [Epub ahead of print]
TRAIL has been extensively explored as a cancer drug based on its tumor-selective activity profile but it is incapable per se of discriminating between death receptors expressed by normal host cells and transformed cancer cells. Furthermore, it is well documented that surface tethering substantially increases its biologic activity. We have previously reported on Meso-TR3, a constitutive TRAIL trimer targeted to the biomarker MUC16 (CA125), in which the entire ectodomain of human mesothelin was genetically fused to the TR3 platform, facilitating attachment to the cancer cells via the MUC16 receptor. Here, we designed a truncation variant, in which the minimal 64 amino acid MUC16 binding domain of mesothelin was incorporated into TR3. It turned out that the dual-domain biologic Meso64-TR3 retained its high MUC16 affinity and bound to the cancer cells quickly, independent of the TR3/death receptor interaction. Furthermore, it was substantially more potent than Meso-TR3 and TR3 in vitro and in a preclinical xenograft model of MUC16-dependent ovarian cancer.
4.Identification of lipid-phosphatidylserine (PS) as the target of unbiasedly selected cancer specific peptide-peptoid hybrid PPS1.
Desai TJ1, Toombs JE2, Minna JD2,3,4,5, Brekken RA2,3,4,6, Udugamasooriya DG1,7. Oncotarget. 2016 Apr 22. doi: 10.18632/oncotarget.8929. [Epub ahead of print]
Phosphatidylserine (PS) is an anionic phospholipid maintained on the inner-leaflet of the cell membrane and is externalized in malignant cells. We previously launched a careful unbiased selection targeting biomolecules (e.g. protein, lipid or carbohydrate) distinct to cancer cells by exploiting HCC4017 lung cancer and HBEC30KT normal epithelial cells derived from the same patient, identifying HCC4017 specific peptide-peptoid hybrid PPS1. In this current study, we identified PS as the target of PPS1. We validated direct PPS1 binding to PS using ELISA-like assays, lipid dot blot and liposome based binding assays. In addition, PPS1 recognized other negatively charged and cancer specific lipids such as phosphatidic acid, phosphatidylinositol and phosphatidylglycerol. PPS1 did not bind to neutral lipids such as phosphatidylethanolamine found in cancer and phosphatidylcholine and sphingomyelin found in normal cells. Further we found that the dimeric version of PPS1 (PPS1D1) displayed strong cytotoxicity towards lung cancer cell lines that externalize PS, but not normal cells.
