HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity

Sharma, Vivek; Koul, Nitin; Joseph, Christy; Dixit, Deobrat; Ghosh, Sadashib; Sen, Ellora

doi:10.1111/j.1582-4934.2009.00844.x

Cited by 50 publications

(32 citation statements)

References 37 publications

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“…We conclude that, although affected mitochondrial pro-and anti-apoptotic proteins may differ between HDAC inhibitory compounds, a perturbation of proand antiapoptic mitochondrial proteins might be a biological prerequisite for the cytotoxic effect of HDACi in MM. Regarding the upregulation of pJNK, our results are in agreement with those of others (Dasmahapatra et al, 2010;Sharma et al, 2010), who have reported JNK activation upon incubation with HDACi in diffuse large cell lymphomas and gliomas, respectively. We further analysed the modulation of signalling pathways underlying CR2408-induced apoptosis and cell cycle arrest.…”

Section: Discussionsupporting

confidence: 93%

The pan‐histone deacetylase inhibitor CR2408 disrupts cell cycle progression, diminishes proliferation and causes apoptosis in multiple myeloma cells

et al. 2011

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SummaryIn view of the fact that histone deacetylases (HDACs) are promising targets for myeloma therapy, we investigated the effects of the HDAC inhibitor CR2408 on multiple myeloma (MM) cells in vitro. CR2408 is a direct pan-HDAC inhibitor and inhibits all known 11 HDACs with a 50% inhibitory concentration (IC 50 ) of 12 nmol/l (HDAC 6) to 520 nmol/l (HDAC 8). Correspondingly, CR2408 induces hyperacetylation of histone H4, inhibits cell growth and strongly induces apoptosis (IC 50 = 0AE1-0AE5 lmol/l) in MM cell lines and primary MM cells. CR2408 leads to fragmentation of cells and induces an accumulation in the subG1 phase accompanied with moderately decreased levels of cyclin D1 and cdk4 and strongly decreased levels of cdc25a, pRb and p53. Interruption of the cell cycle is reflected by inhibition of cell proliferation and is accompanied by decreased phosphorylation of 4E-BP1 and p70S6k. Treatment with CR2408 results in increased protein levels of Bim and pJNK and downregulation of Bad and Bcl-xL and activation of Caspases 3, 8 and 9. Furthermore, as HDAC inhibitors have shown synergism with other drugs, these effects were investigated and synergism was observed for combinations of CR2408 with doxorubicin and bortezomib. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor that gives further insights into the biological sequelae of HDAC inhibition in MM.

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Section: Discussionsupporting

confidence: 93%

The pan‐histone deacetylase inhibitor CR2408 disrupts cell cycle progression, diminishes proliferation and causes apoptosis in multiple myeloma cells

et al. 2011

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“…Indeed, all three compounds effectively suppressed the ATF6 pathway to the same extent. Previous reports have indicated the potential of HDAC inhibitors to activate JNK via generation of reactive oxygen species or deacetylation-mediated inhibition of mitogen-activated protein kinase phosphatase 1 (Yu et al, 2003;Chi and Flavell, 2008;Sharma et al, 2010). The kinase activity of IRE1α, indicated by JNK phosphorylation, was inhibited by 2-POAA-NO2 most effectively, with 2-POAA-OMe and 2-NOAA being less potent.…”

Section: Discussionmentioning

confidence: 95%

Selective, potent blockade of the IRE1 and ATF6 pathways by 4‐phenylbutyric acid analogues

Zhang

Nakajima

Kato

et al. 2013

British J Pharmacology

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“…There is strong preclinical evidence to suggest that HDAC inhibitors (HDACi) have anti-neoplastic and anti-angiogenic effects in HGG. HDAC inhibition promotes growth arrest and apoptotic cells death in glioma models [10][11][12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma

et al. 2011

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Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

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HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity

Cited by 50 publications

References 37 publications

The pan‐histone deacetylase inhibitor CR2408 disrupts cell cycle progression, diminishes proliferation and causes apoptosis in multiple myeloma cells

The pan‐histone deacetylase inhibitor CR2408 disrupts cell cycle progression, diminishes proliferation and causes apoptosis in multiple myeloma cells

Selective, potent blockade of the IRE1 and ATF6 pathways by 4‐phenylbutyric acid analogues

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma

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