title: Disabling c-Myc in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadruplex interactive agent S2T1-6OTD.
abstract: We investigated here the effects of S2T1-6OTD, a novel telomestatin derivative that is synthesized to target G-quadruplex-forming DNA sequences, on a representative panel of human medulloblastoma (MB) and atypical teratoid/rhabdoid (AT/RT) childhood brain cancer cell lines. S2T1-6OTD proved to be a potent c-Myc inhibitor through its high-affinity physical interaction with the G-quadruplex structure in the c-Myc promoter. Treatment with S2T1-6OTD reduced the mRNA and protein expressions of c-Myc and hTERT, which is transcriptionally regulated by c-Myc, and decreased the activities of both genes. In remarkable contrast to control cells, short-term (72-hour) treatment with S2T1-6OTD resulted in a dose- and time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC(50), 0.25-0.39 micromol/L). Under conditions where inhibition of both proliferation and c-Myc activity was observed, S2T1-6OTD treatment decreased the protein expression of the cell cycle activator cyclin-dependent kinase 2 and induced cell cycle arrest. Long-term treatment (5 weeks) with nontoxic concentrations of S2T1-6OTD resulted in a time-dependent (mainly c-Myc-dependent) telomere shortening. This was accompanied by cell growth arrest starting on day 28 followed by cell senescence and induction of apoptosis on day 35 in all of the five cell lines investigated. On in vivo animal testing, S2T1-6OTD may well represent a novel therapeutic strategy for childhood brain tumors.
authors.affiliation: Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Hürlimann
authors.forename: Giulio
authors.initials: G
authors.lastname: Fiaschetti
authors.forename: Deborah
authors.initials: D
authors.lastname: Castelletti
authors.forename: Tera
authors.initials: T
authors.lastname: Masayuki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
authors.forename: Ilian
authors.initials: I
authors.lastname: Jelesarov
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-ya
authors.forename: Michael
authors.initials: M
authors.lastname: Grotzer
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008527:Medulloblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000473:pathology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013724:Teratoma / Q000473:pathology*; D013997:Time Factors
chemical_list: D010080:Oxazoles; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D051357:Cyclin-Dependent Kinase 2; D019098:Telomerase