Regulation of epidermal growth factor receptor signaling by plasmid-based microRNA-7 inhibits human malignant gliomas growth and metastasis in vivo.

MicroRNAs are endogenous, non-coding RNAs of approximately 20-22 nucleotides that regulate genes expression by binding to the 3' untranslated region (UTR) of targets mRNAs and play critical roles in cancer pathways. Malignant glioma is the most common and highly lethal central nervous system tumor for which little effective treatment is available over several decades. The purpose of this study was to explore the therapeutic potential of plasmid-based microRNA-7 (miR-7) for gliomas in vivo. Enhancing miR-7 levels in vitro could significantly induce cell apoptosis, and inhibit cell proliferation, cell migration and invasion. Western blotting analysis was performed, which indicated that miR-7 directly inhibited epidermal growth factor receptor (EGFR) and further antagonized the downstream protein kinases including ERK, Akt and Stat3. Furthermore, systemic administration of miR-7 encapsulated in cationic liposome resulted in glioma xenografts growth arrest and the metastatic nodules decrease effectively in a sequence-specific manner. In this study, miR-7 was applied in glioma treatment for the first time in vivo. Our findings suggested that the plasmid-mediated gene therapy with miR-7 appeared to be a promising candidate for the development of new antitumor and anti-metastasis treatment for human glioma.

IL15 combined with Caspy2 provides enhanced therapeutic efficiency against murine malignant neoplasm growth and metastasis.

Interleukin-15 (IL15) is a potential immunotherapeutic treatment for cancer. Caspy2 is an active zebra caspase for inducing apoptosis and immune response in murine tumors. In this study, we aim to evaluate the potential of gene therapy using IL15 and Caspy2 against the murine tumors. Plasmid expressing both Caspy2 and IL15 genes was constructed, encapsulated in DOTAP/cholesterol cationic liposome and injected intratumorally into the mice bearing CT26, B16-F10 and 4T1 carcinoma. We found that coexpression of IL15 and Caspy2 could significant inhibit tumor growth and prolong survival of the mice bearing CT26 or B16F10 tumor. A significant reduction in spontaneous lung metastasis was observed in the 4T1 tumor model. In CT26 model, the mice treated with IL15 and Caspy2 acquired a long-time protective immunity against the parental tumor cell rechallenge. Cytotoxic T lymphocytes and terminal deoxynucleotidyltransferase-mediated nick end labelling assays showed that the combination of capsy2 and IL15 could enhance both the apoptosis and immune response induction, which may account for its extraordinary antitumor effect. Furthermore, we showed that the observed tumor suppression by IL15 and Caspy2 concurred with the Caspy2-mediated downregulation of IL10 and upregulation of interferon-γ and tumor necrosis factor-α. Our results therefore suggested that the combination regimen might be a novel and effective strategy for cancer treatment.

Highly diastereoselective synthesis of vinylcyclopropane derivatives with (-)-8-phenylmenthol as chiral auxiliary.

The silylated telluronium allylide 4, generated in situ from the corresponding telluronium salt in the presence of LiTMP, reacted with (-)-8-phenylmenthyl alpha,beta-unsaturated esters to afford trans-2-silylvinyl-trans-3-substituted cyclopropyl esters with high diastereoselectivity in high yields. The absolute configuration was determined by chemical transformation. A mechanistic rationale is proposed.

Importance of planar chirality in chiral catalysts with three chiral elements: the role of planar chirality in 2'-substituted 1,1'-P,N-ferrocene ligands on the enantioselectivity in Pd-catalyzed allylic substitution.

A series of novel planar chiral 2'-substituted 1,1'-P,N-ferrocene ligands 9-11, 14, and 16 were prepared with diastereopurity >99:1 and found to be effective in asymmetric allylic alkylation and amination reactions. Ligand 14 furnished the highest enantiomeric excess, 98.5% and 96.5% ee in alkylation and amination reactions, respectively. The role of planar chirality in asymmetric reactions has been examined, and decisive effects on enantioselectivity as well as the control of absolute configuration in palladium-catalyzed allylic alkylation and amination reactions were observed. To clarify why and how the planar chirality governed the stereochemical outcome, X-ray crystallographic structures of eta(3)-diphenylallyl Pd complexes, (1)H NMR, (31)P NMR spectra of palladium dichloride complexes, and eta(3)-diphenylallyl Pd complexes of three 1,1'-P,N-ferrocene ligands were analyzed with the aid of COSY and 2D NOESY experiments. All results led to the conclusion that planar chirality influences the stereochemical outcome by changing or even inverting the ratio of two rotamers because of the steric interaction between a planar chiral group and the coordination site.

Highly efficient ligands for palladium-catalyzed asymmetric alkylation of ketone enolates.

[figure: see text] Ferrocene-modified chiral pocket ligands have been studied in the palladium-catalyzed asymmetric alkylation of simple ketone enolates, in which (R,R,Sp,Sp)-1 containing two pairs of matched chiralities, central chirality and planar chirality, behaved very efficiently in this reaction and up to 95% ee value was achieved.