Disablingc-Mycin 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 doseand time-dependent antiproliferative effect in all MB and AT/RT brain tumor cell lines tested (IC 50 , 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.

A Sensitized RNA Interference Screen Identifies a Novel Role for the PI3K p110γ Isoform in Medulloblastoma Cell Proliferation and Chemoresistance

“…DAOY medulloblastoma cells were transfected with a 96-well plate arrayed library of siRNA duplexes targeting each of the 719 human kinase genes. We chose the DAOY cell line for the screen, as well as UW-228 and PFSK cell lines for validation experiments, because our previous published work has characterized these cell lines in terms of response to cisplatin and activation of various survival pathways (11,19,(22)(23)(24). The characteristics of the cell lines under study are described in the Supplementary Table S1.…”

Human telomerase inhibitors from microbial source

“…a Rubromycin and its analogues, b Chrolactomycin Tauchi et al 2003). The effect of telomestatin has been tested in various cancer types and it showed potent anti proliferative activity in multiple myeloma, leukemia, neuroblastoma, human medulloblastoma and atypical teratoid/ rhabdoid cell lines in vitro Binz et al 2005;Shalaby et al 2010). It has been tested in xenograph mouse model in vivo also (Tauchi et al 2006).…”

Advances in Molecular Targets for the Treatment of Medulloblastomas

“…Several studies have investigated the therapeutic potential of targeting the c-MYC gene in medulloblastomas. One example of this targeting is the Telomestatin derivative, S2T1-6OTD, which binds to the NHEIII1 sequence in the promoter of c-MYC impairing transcriptional activation and thereby decreasing the viability of medulloblastoma cells [76]. S2T1-6OTD also inhibits the expression of the human hTERT gene required for telomere maintenance [76].…”

“…One example of this targeting is the Telomestatin derivative, S2T1-6OTD, which binds to the NHEIII1 sequence in the promoter of c-MYC impairing transcriptional activation and thereby decreasing the viability of medulloblastoma cells [76]. S2T1-6OTD also inhibits the expression of the human hTERT gene required for telomere maintenance [76]. Other agents, such as the natural-occurring plant derived polyphenol, Resveratrol (3, 5, 4!-trihydroxy-trans-stilbene), the anticonvulsant and histone acetylase inhibitor, Valproic acid, the uassinoid analogue, NBT-272, and all-trans-retinoic acid, can all e ectively inhibit the c-MYC gene expression and subsequently the in vitro and in vi o growth of medulloblastoma cells [74,[77][78][79].…”