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.

doi:10.1158/1535-7163.mct-14-0113

Cited by 23 publications

(16 citation statements)

References 31 publications

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“…Neurosphere forming cells, which form neurosphere were kind gift from Dr. Jann N. Sarkaria. For neurosphere formation, cells were plated on laminin coated plate and maintained in serum free media consisting of Knockout DMEM/F12 media supplemented with 2% serum free media supplement, 2% L-glutamine, 1% penicillin/streptomycin, 20 ng/ml EFG and 20 ng/ml FGF, as described previously [29]. …”

Section: Methodsmentioning

confidence: 99%

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Ranjan

Srivastava

2017

Oncotarget

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Glioblastoma (GBM) is the most common brain tumor with poor survival rate. Our results show that penfluridol, an antipsychotic drug significantly reduced the survival of ten adult and pediatric glioblastoma cell lines with IC50 ranging 2–5 μM after 72 hours of treatment and induced apoptosis. Penfluridol treatment suppressed the phosphorylation of Akt at Ser473 and reduced the expression of GLI1, OCT4, Nanog and Sox2 in several glioblastoma cell lines in a concentration-dependent manner. Inhibiting Akt with LY294002 and siRNA, or inhibiting GLI1 using GANT61, cyclopamine, siRNA and CRISPR/Cas9 resulted in enhanced cell growth suppressive effects of penfluridol. On the other hand, overexpression of GLI1 significantly attenuated the effects of penfluridol. Our results further demonstrated that penfluridol treatment inhibited the growth of U87MG tumors by 65% and 72% in subcutaneous and intracranial in vivo glioblastoma tumor models respectively. Immunohistochemical and western blot analysis of tumors revealed reduced pAkt (Ser 473), GLI1, OCT4 and increase in caspase-3 cleavage and TUNEL staining, confirming in vitro findings. Taken together, our results indicate that overall glioblastoma tumor growth suppression by penfluridol was associated with Akt-mediated inhibition of GLI1.

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Section: Methodsmentioning

confidence: 99%

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Ranjan

Srivastava

2017

Oncotarget

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“…However, TMZ resistance of GBM is a key factor involved in poor responses and dismal prognosis. Previous studies have evidenced that the resistance to TMZ of molecular pathogenes in GBM is related to O6-methylguanine-DNA methyltransferase (MGMT), which can lead to the replication of DNA and the growth of GBM cells (7,8).…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Lan

Yang

Han

et al. 2015

International Journal of Oncology

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Abstract. The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC 50 ) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC 50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

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“…3D). Together with multiple studies reporting expression of ATR in glioma cell lines [37–40] we chose U251 MG, a cell line with high ATR mRNA expression [41,42], as a mouse model for our in vitro / in vivo studies. The mRNA level of ATR in GBM, although significantly higher in comparison to healthy brain tissues [41,42], are lower than other major solid tumors such as squamous cell lung, breast, colorectal, pancreatic, prostate, and skin cancer, as well as most of the remaining cancer types (Suppl.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of [ 18 F]-ATRi as PET tracer for in vivo imaging of ATR in mouse models of brain cancer

Carlucci

Carney

Ahmad

et al. 2017

Nuclear Medicine and Biology

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Rationale Ataxia telangiectasia and Rad3-related (ATR) threonine serine kinase is one of the key elements in orchestrating the DNA damage response (DDR). As such, inhibition of ATR can amplify the effects of chemo- and radiation-therapy, and several ATR inhibitors (ATRi) have already undergone clinical testing in cancer. For more accurate patient selection, monitoring and staging, real-time in vivo imaging of ATR could be invaluable; the development of appropriate imaging agents has remained a major challenge. Methods 3-amino-N-(4-[18F]phenyl)-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxamide ([18F]-ATRi), a close analogue of Ve-821, (a clinical ATRi candidate), was readily accomplished similarly to already established synthetic procedures. Structurally, 18F was introduced at the 4-position of the aromatic ring of Ve-821 for generating a labeled ATR inhibitor. In vitro experiments were conducted in U251MG glioblastoma cell lines and ex vivo biodistribution were performed in subcutaneous U251 MG xenograft bearing athymic nude mice following microPET imaging. Results [18F]-ATRi has a similar pharmacokinetic profile to that of Ve-821. Using an U251 MG glioblastoma mouse model, we evaluated the in vivo binding efficiency of [18F]-ATRi. Blood and tumor showed a statistically significant difference between mice injected with only the probe or following blocking experiment with Ve-821 (1.48 ± 0.40%ID/g vs. 0.46 ± 0.12%ID/g in tumor and 1.85 ± 0.47%ID/g vs. 0.84 ± 0.3%ID/g in blood respectively). Conclusions [18F]-ATRi represents the first 18F positron emission tomography (PET) ATR imaging agent, and is designed on a low nanomolar and clinically relevant ATR inhibitor.

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Evaluation of Novel Imidazotetrazine Analogues Designed to Overcome Temozolomide Resistance and Glioblastoma Regrowth

Cited by 23 publications

References 31 publications

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Penfluridol suppresses glioblastoma tumor growth by Akt-mediated inhibition of GLI1

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Evaluation of [ 18 F]-ATRi as PET tracer for in vivo imaging of ATR in mouse models of brain cancer

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