Iated cells. Irradiation has been shown to upregulate telomerase activity in several cell lines (35,50-53) which includes a glioblastoma cell line (46). AKT is able to phosphorylate hTERT, the catalytic subunit of telomerase and activate telomerase activity (47). Lately, AKT has been also shown to facilitate nuclear import of hTERT (82). Additionally, ionizing radiation has been reported to upregulate telomerase activity in cancer cell lines by post-translational mechanism via the PI3K/AKT pathway (54). Whilst Ly-294002 decreased telomerase activity in unirradiated CB193 and T98G cells, concomitantly with AKT dephosphorylation and G1 arrest, we’ve shown that it didn’t avert the radiation-induced improve of telomerase activity, which was not correlated with a rise of AKT phosphorylation in these cell lines. These outcomes rule out a predominant role of your PI3K/AKT pathway within the radiationinduced upregulation of telomerase activity in our glioma cells lines suggesting that an option pathway is involved which remains to become determined. Such AKT/PKB independent upregulation of telomerase activity soon after irradiation have been currently observed in other cell lines (83) but associated with delayed DSB repair. Complementary research of DSB repair-related molecules are needed in our model. Telomerase is thought to boost the radiation resistance of cancer cells by either safeguarding nNOS Inhibitor Biological Activity telomeres from fusion or by its anti-apoptotic functions or by promoting DNA repair through its actions on the chromatin structure (11,34-36,8487). A telomerase antagonist, imetelstat in combination with radiation and temozolomide had a dramatic impact on cell survival of key human glioblastoma tumor-initiating cells (45). Telomere targeting having a G-quadruplex ligand, has been recently reported to enhance radiation-induced killing of human glioblastoma cells (44). The personalization of glioblastoma medicine about telomere profiling in radiation therapy is currently under study (88), and might be extended to telomerase activity. Our benefits showing that telomerase upregulation was not abolished by the PI3K/AKT pathway inhibition, suggests that personalized combined therapies associating PI3K and telomerase inhibitors or telomere G-quadruplex ligands must be deemed to enhance the radiosensitization in telomerase expressing high-grade gliomas.
NIH Public AccessAuthor ManuscriptAngew Chem Int Ed Engl. Author manuscript; available in PMC 2014 May 10.Published in final edited form as: Angew Chem Int Ed Engl. 2013 May possibly ten; 52(20): . doi:ten.1002/anie.201301741.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptA Catalytic Asymmetric Synthesis of Polysubstituted Piperidines αvβ3 Antagonist Biological Activity Employing a Rhodium (I) Catalyzed [2+2+2] Cycloaddition Employing a Cleavable TetherTimothy J. Martin and Tomislav Rovis Division of Chemistry, Colorado State University Fort Collins, CO 80523 (USA)AbstractAn enantioselective rhodium (I) catalyzed [2+2+2] cycloaddition using a cleavable tether has been developed. The reaction proceeds with a variety of alkyne substrates in good yield and high enantioselectivity. Upon reduction with the vinylogous amide in higher diastereoselectivity (19:1) and cleavage in the tether, N-methylpiperidine solutions with functional group handles can be accessed.Keywords and phrases Asymmetric synthesis; Heterocyclic compd; Cycloaddition react As a consequence of their prevalence in drug targets and natural goods, the asymmetric synthesis of nitrogen containing heterocycles i.