Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth

Yulian P. Ramirez, Ann C. Mladek, Roger M. Phillips, Mikko Gynther, Jarkko Rautio, Alonzo H. Ross, Richard T. Wheelhouse, Jann N. Sakaria

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions. DP68-induced interstrand DNA cross-links were demonstrated with H2O2-treated cells. Furthermore, DP68 induced a distinct cell-cycle arrest with accumulation of cells in S phase that is not observed for TMZ. Consistent with this biologic response, DP68 induces a strong DNA damage response, including phosphorylation of ATM, Chk1 and Chk2 kinases, KAP1, and histone variant H2AX. Suppression of FANCD2 expression or ATR expression/kinase activity enhanced anti-glioblastoma effects of DP68. Initial pharmacokinetic analysis revealed rapid elimination of these drugs from serum. Collectively, these data demonstrate that DP68 is a novel and potent antiglioblastoma compound that circumvents TMZ resistance, likely as a result of its independence from MGMT and mismatch repair and its capacity to cross-link strands of DNA.

LanguageEnglish
Pages111-119
Number of pages9
JournalMolecular Cancer Therapeutics
Volume14
Issue number1
Early online date28 Oct 2014
DOIs
Publication statusPublished - 1 Jan 2015
Externally publishedYes

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temozolomide
Glioblastoma
Cell Line
DNA Mismatch Repair
DNA
Cell Cycle Checkpoints
S Phase
Histones
DNA Damage
Phosphotransferases
Pharmacokinetics
Phosphorylation

Cite this

Ramirez, Yulian P. ; Mladek, Ann C. ; Phillips, Roger M. ; Gynther, Mikko ; Rautio, Jarkko ; Ross, Alonzo H. ; Wheelhouse, Richard T. ; Sakaria, Jann N. / Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 1. pp. 111-119.
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Evaluation of novel imidazotetrazine analogues designed to overcome temozolomide resistance and glioblastoma regrowth. / Ramirez, Yulian P.; Mladek, Ann C.; Phillips, Roger M.; Gynther, Mikko; Rautio, Jarkko; Ross, Alonzo H.; Wheelhouse, Richard T.; Sakaria, Jann N.

In: Molecular Cancer Therapeutics, Vol. 14, No. 1, 01.01.2015, p. 111-119.

Research output: Contribution to journalArticle

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