Limits...
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

Growth inhibition of MPNST cell lines S462 and S520 Cells were plated at a density of 15000/well on 12 mm coverslips and treated with indicated concentrations of Exisulind and Sulindac Sulfide for 48 h and 96 h. Cell growth was measured by BrdU-incorporation. The final DMSO concentration used here did not exceed 0.2% and had no effect on cell growth. The values represent the means and standard deviations of triplicates.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC425591&req=5

Figure 1: Growth inhibition of MPNST cell lines S462 and S520 Cells were plated at a density of 15000/well on 12 mm coverslips and treated with indicated concentrations of Exisulind and Sulindac Sulfide for 48 h and 96 h. Cell growth was measured by BrdU-incorporation. The final DMSO concentration used here did not exceed 0.2% and had no effect on cell growth. The values represent the means and standard deviations of triplicates.

Mentions: Exisulind and Sulindac Sulfide were examined for their ability to inhibit growth of two MPNST cell lines. Exisulind was added to the media at a final concentration of 100, 250 and 500 μM and Sulindac Sulfide of 50, 100 and 125 μM. Both Sulindac derivatives exhibited a dramatic dose-dependent growth inhibition of the two MPNST derived cell lines (Fig. 1). This effect was more apparent after 4 days of treatment than after 2 days (Fig. 1). The corresponding mean IC50 values of both cell lines after 96 h of treatment were 120 μM for Exisulind, and 63 μM for Sulindac Sulfide. The proliferation rate of cells did not change when the medium was supplemented with DMSO at concentrations used in drug treatment (0.2%).


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)

Growth inhibition of MPNST cell lines S462 and S520 Cells were plated at a density of 15000/well on 12 mm coverslips and treated with indicated concentrations of Exisulind and Sulindac Sulfide for 48 h and 96 h. Cell growth was measured by BrdU-incorporation. The final DMSO concentration used here did not exceed 0.2% and had no effect on cell growth. The values represent the means and standard deviations of triplicates.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Growth inhibition of MPNST cell lines S462 and S520 Cells were plated at a density of 15000/well on 12 mm coverslips and treated with indicated concentrations of Exisulind and Sulindac Sulfide for 48 h and 96 h. Cell growth was measured by BrdU-incorporation. The final DMSO concentration used here did not exceed 0.2% and had no effect on cell growth. The values represent the means and standard deviations of triplicates.
Mentions: Exisulind and Sulindac Sulfide were examined for their ability to inhibit growth of two MPNST cell lines. Exisulind was added to the media at a final concentration of 100, 250 and 500 μM and Sulindac Sulfide of 50, 100 and 125 μM. Both Sulindac derivatives exhibited a dramatic dose-dependent growth inhibition of the two MPNST derived cell lines (Fig. 1). This effect was more apparent after 4 days of treatment than after 2 days (Fig. 1). The corresponding mean IC50 values of both cell lines after 96 h of treatment were 120 μM for Exisulind, and 63 μM for Sulindac Sulfide. The proliferation rate of cells did not change when the medium was supplemented with DMSO at concentrations used in drug treatment (0.2%).

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