title: Contribution of telomere G-quadruplex stabilization to the inhibition of telomerase-mediated telomere extension by chemical ligands.
abstract: Inhibition of telomerase activity through stabilizing telomere G-quadruplex with small chemical ligands is emerging as a novel strategy for cancer therapy. For the large number of ligands that have been reported to inhibit telomerase activity, it is difficult to validate the contribution of G-quadruplex stabilization to the overall inhibition. Using a modified telomere repeat amplification protocol (TRAP) method to differentiate the telomere G-quadruplex independent effect from dependent ones, we analyzed several ligands that have high affinity and/or selectivity to telomere G-quadruplex. Our results show that these ligands effectively inhibited telomerase activity in the absence of telomere G-quadruplex. The expected G-quadruplex-dependent inhibition was only obvious for the cationic ligands at low K(+) concentration, but it dramatically decreased at physiological concentration of K(+). These observations demonstrate that the ligands are much more than G-quadruplex stabilizers with a strong G-quadruplex-irrelevant off-target effect. They inhibit telomerase via multiple pathways in which stabilization of telomere G-quadruplex may only make a minor or neglectable contribution under physiologically relevant conditions depending on the stability of telomere G-quadruplex under ligand-free conditions.
authors.affiliation: Laboratory of Biochemistry and Biophysics, College of Life Sciences, Wuhan University, Wuhan, P R China.
authors.forename: Chang-yue
authors.initials: CY
authors.lastname: Chen
authors.forename: Quan
authors.initials: Q
authors.lastname: Wang
authors.forename: Jia-quan
authors.initials: JQ
authors.lastname: Liu
authors.forename: Yu-hua
authors.initials: YH
authors.lastname: Hao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
mesh_terms: D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054856:G-Quadruplexes; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000737:chemistry*
chemical_list: C486012:3,6-bis(1-methyl-4-vinylpyridium)carbazole diiodide; D002227:Carbazoles; D007211:Indoles; D008024:Ligands; D009942:Organometallic Compounds; D011726:Pyridinium Compounds; C028418:tetrasulfophthalocyanine; D019098:Telomerase