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Disabling c-Myc in Childhood Medulloblastoma and Atypical Teratoid/Rhabdoid Tumor Cells by the Potent G-Quadruplex Interactive Agent S2T1-6OTD


Shalaby, T; et al; Nagasawa, K; Jelesarov, I (2010). Disabling c-Myc in Childhood Medulloblastoma and Atypical Teratoid/Rhabdoid Tumor Cells by the Potent G-Quadruplex Interactive Agent S2T1-6OTD. Molecular Cancer Therapeutics, 9(1):167-169.

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 doseand
time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC50, 0.25–
0.39 μmol/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.

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 doseand
time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC50, 0.25–
0.39 μmol/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.

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34 citations in Web of Science®
35 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry

04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:January 2010
Deposited On:17 Mar 2010 13:12
Last Modified:05 Apr 2016 14:02
Publisher:American Association for Cancer Research
ISSN:1535-7163
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1535-7163.MCT-09-0586
PubMed ID:20053783

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