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Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients.

Frahm S, Kurtz A, Kluwe L, Farassati F, Friedrich RE, Mautner VF - Cancer Cell Int. (2004)

Bottom Line: The decrease in viability of the tested cells correlated with induction of apoptosis.Treatment with 500 microM Exisulind and 125 microM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells.Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Brain Tumor Biology, Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany. sfrahm@uke.uni-hamburg.de

ABSTRACT
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms leading to death in most cases. Patients with Neurofibromatosis type 1 have an increased risk of developing this malignancy. The metabolites of the inactive prodrug Sulindac, Sulindac Sulfide and Sulindac Sulfone (Exisulind) are new chemopreventive agents that show promising results in the treatment of different cancer types. In this study we examined the antineoplastic effect of these compounds on primary cells derived from two MPNSTs of Neurofibromatosis type 1 patients. RESULTS: Exisulind and Sulindac Sulfide showed a dramatic time- and dose-dependent growth inhibitory effect with IC50-values of 120 microM and 63 microM, respectively. The decrease in viability of the tested cells correlated with induction of apoptosis. Treatment with 500 microM Exisulind and 125 microM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells. Reduced expression of RAS-GTP and phosphorylated ERK1/2 was detected in treated MPNST cells. Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen. CONCLUSIONS: Our results suggest that this class of compounds may be of therapeutic benefit for Neurofibromatosis type 1 patients with MPNST.

No MeSH data available.


Related in: MedlinePlus

Activation of SAPK/JNK but not caspase-3 after treatment with Sulindac metabolites The activation of phospho-SAPK/JNK (dimer: 46 kD + 54 kD) reached the highest level after 24 h of treatment with Exisulind (Exi) and Sulindac Sulfide (s. s.), but no effect was seen on cleaved caspase-3 activation. DHA did not have any effect on neither JNK nor caspase-3 activation. Cell line S462 was grown in DMEM with 10% serum and treated at 80–90% confluency with 0.2% DMSO, 500 μM Exisulind (Exi) or 125 μM Sulindac Sulfide (s. s.) and blots were incubated with either phosphorylated SAPK/JNK or cleaved caspase-3 antibody. The positive control for caspase activation is a mouse MPNST cell line treated 7 h with 30 μM DHA.
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Figure 6: Activation of SAPK/JNK but not caspase-3 after treatment with Sulindac metabolites The activation of phospho-SAPK/JNK (dimer: 46 kD + 54 kD) reached the highest level after 24 h of treatment with Exisulind (Exi) and Sulindac Sulfide (s. s.), but no effect was seen on cleaved caspase-3 activation. DHA did not have any effect on neither JNK nor caspase-3 activation. Cell line S462 was grown in DMEM with 10% serum and treated at 80–90% confluency with 0.2% DMSO, 500 μM Exisulind (Exi) or 125 μM Sulindac Sulfide (s. s.) and blots were incubated with either phosphorylated SAPK/JNK or cleaved caspase-3 antibody. The positive control for caspase activation is a mouse MPNST cell line treated 7 h with 30 μM DHA.

Mentions: The stress-activated protein kinase/ Jun-terminal kinase SAPK/JNK, a mediator of apoptosis, was activated (phosphorylated) 16 h after treatment with either of the Sulindac metabolites (not shown), and increased further after 24 h and 48 h (Fig. 6). Treatment with DHA, a drug known to induce apoptosis in mouse MPNST cells (personal communication of Andreas Kurtz) had no effect on phosphorylation of this protein.


Sulindac derivatives inhibit cell growth and induce apoptosis in primary cells from malignant peripheral nerve sheath tumors of NF1-patients.

Frahm S, Kurtz A, Kluwe L, Farassati F, Friedrich RE, Mautner VF - Cancer Cell Int. (2004)

Activation of SAPK/JNK but not caspase-3 after treatment with Sulindac metabolites The activation of phospho-SAPK/JNK (dimer: 46 kD + 54 kD) reached the highest level after 24 h of treatment with Exisulind (Exi) and Sulindac Sulfide (s. s.), but no effect was seen on cleaved caspase-3 activation. DHA did not have any effect on neither JNK nor caspase-3 activation. Cell line S462 was grown in DMEM with 10% serum and treated at 80–90% confluency with 0.2% DMSO, 500 μM Exisulind (Exi) or 125 μM Sulindac Sulfide (s. s.) and blots were incubated with either phosphorylated SAPK/JNK or cleaved caspase-3 antibody. The positive control for caspase activation is a mouse MPNST cell line treated 7 h with 30 μM DHA.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC425591&req=5

Figure 6: Activation of SAPK/JNK but not caspase-3 after treatment with Sulindac metabolites The activation of phospho-SAPK/JNK (dimer: 46 kD + 54 kD) reached the highest level after 24 h of treatment with Exisulind (Exi) and Sulindac Sulfide (s. s.), but no effect was seen on cleaved caspase-3 activation. DHA did not have any effect on neither JNK nor caspase-3 activation. Cell line S462 was grown in DMEM with 10% serum and treated at 80–90% confluency with 0.2% DMSO, 500 μM Exisulind (Exi) or 125 μM Sulindac Sulfide (s. s.) and blots were incubated with either phosphorylated SAPK/JNK or cleaved caspase-3 antibody. The positive control for caspase activation is a mouse MPNST cell line treated 7 h with 30 μM DHA.
Mentions: The stress-activated protein kinase/ Jun-terminal kinase SAPK/JNK, a mediator of apoptosis, was activated (phosphorylated) 16 h after treatment with either of the Sulindac metabolites (not shown), and increased further after 24 h and 48 h (Fig. 6). Treatment with DHA, a drug known to induce apoptosis in mouse MPNST cells (personal communication of Andreas Kurtz) had no effect on phosphorylation of this protein.

Bottom Line: The decrease in viability of the tested cells correlated with induction of apoptosis.Treatment with 500 microM Exisulind and 125 microM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells.Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Brain Tumor Biology, Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany. sfrahm@uke.uni-hamburg.de

ABSTRACT
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are neoplasms leading to death in most cases. Patients with Neurofibromatosis type 1 have an increased risk of developing this malignancy. The metabolites of the inactive prodrug Sulindac, Sulindac Sulfide and Sulindac Sulfone (Exisulind) are new chemopreventive agents that show promising results in the treatment of different cancer types. In this study we examined the antineoplastic effect of these compounds on primary cells derived from two MPNSTs of Neurofibromatosis type 1 patients. RESULTS: Exisulind and Sulindac Sulfide showed a dramatic time- and dose-dependent growth inhibitory effect with IC50-values of 120 microM and 63 microM, respectively. The decrease in viability of the tested cells correlated with induction of apoptosis. Treatment with 500 microM Exisulind and 125 microM Sulindac Sulfide for a period of 2 days increased the rate of apoptosis 21-27-fold compared to untreated cells. Reduced expression of RAS-GTP and phosphorylated ERK1/2 was detected in treated MPNST cells. Moreover, elevated levels of phosphorylated SAPK/JNK were found after drug treatment, and low activation of cleaved caspase-3 was seen. CONCLUSIONS: Our results suggest that this class of compounds may be of therapeutic benefit for Neurofibromatosis type 1 patients with MPNST.

No MeSH data available.


Related in: MedlinePlus