Iated cells. Irradiation has been shown to upregulate telomerase activity in different cell lines (35,50-53) like a glioblastoma cell line (46). AKT is in a position 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 PPARĪ± Agonist Storage & Stability pathway (54). Although Ly-294002 decreased telomerase activity in unirradiated CB193 and T98G cells, concomitantly with AKT dephosphorylation and G1 arrest, we’ve got shown that it did not stop the radiation-induced boost of telomerase activity, which was not correlated with a rise of AKT phosphorylation in these cell lines. These results rule out a predominant part with the PI3K/AKT pathway in 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 after irradiation have already been already observed in other cell lines (83) but associated with delayed DSB repair. Complementary research of DSB repair-related molecules are required in our model. Telomerase is believed to increase the radiation resistance of cancer cells by either protecting telomeres from fusion or by its anti-apoptotic functions or by promoting DNA repair via its actions around 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 major human glioblastoma tumor-initiating cells (45). Telomere targeting having a G-quadruplex ligand, has been not too long ago reported to boost radiation-induced killing of human glioblastoma cells (44). The personalization of glioblastoma medicine around telomere profiling in radiation therapy is currently below study (88), and may be extended to telomerase activity. Our results displaying that telomerase upregulation was not abolished by the PI3K/AKT pathway inhibition, suggests that customized combined therapies associating PI3K and telomerase inhibitors or telomere G-quadruplex ligands must be regarded as to enhance the radiosensitization in telomerase expressing high-grade gliomas.
NIH Public AccessAuthor ManuscriptAngew Chem Int Ed Engl. Author manuscript; readily available in PMC 2014 May perhaps ten.Published in final edited form as: Angew Chem Int Ed Engl. 2013 Could 10; 52(20): . doi:10.1002/anie.201301741.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptA Catalytic Asymmetric Synthesis of Polysubstituted Piperidines Employing a Rhodium (I) Catalyzed [2+2+2] Cycloaddition Employing a NK1 Inhibitor Source 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 with a cleavable tether has been developed. The reaction proceeds using a variety of alkyne substrates in good yield and high enantioselectivity. Upon reduction in the vinylogous amide in high diastereoselectivity (19:1) and cleavage from the tether, N-methylpiperidine solutions with functional group handles can be accessed.Keyword phrases Asymmetric synthesis; Heterocyclic compd; Cycloaddition react On account of their prevalence in drug targets and natural goods, the asymmetric synthesis of nitrogen containing heterocycles i.
