Disabling c-Myc in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadruplex interactive agent S2T1-6OTD.
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.
Shalaby
Tarek
T
Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland.
von Bueren
André O
AO
Hürlimann
Marie-Louise
ML
Fiaschetti
Giulio
G
Castelletti
Deborah
D
Masayuki
Tera
T
Nagasawa
Kazuo
K
Arcaro
Alexandre
A
Jelesarov
Ilian
I
Shin-ya
Kazuo
K
Grotzer
Michael
M
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
D010080:Oxazoles; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D051357:Cyclin-Dependent Kinase 2; D019098:Telomerase