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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

Changes in cell morphology characteristic for apoptosis Morphologic changes became evident after 48 h of treatment with 500 μM Exisulind or 125 μM Sulindac Sulfide. A-C: Phase contrast photomicrographs of S462 cells before (A) and after Exisulind (B) treatment. Cell shrinkage, nuclear condensation and formation of apoptotic bodies shown on immunocytochemically labeled cell nuclei with PI after Sulindac Sulfide treatment (C) are classical characteristics of apoptosis and not necrosis.
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Figure 4: Changes in cell morphology characteristic for apoptosis Morphologic changes became evident after 48 h of treatment with 500 μM Exisulind or 125 μM Sulindac Sulfide. A-C: Phase contrast photomicrographs of S462 cells before (A) and after Exisulind (B) treatment. Cell shrinkage, nuclear condensation and formation of apoptotic bodies shown on immunocytochemically labeled cell nuclei with PI after Sulindac Sulfide treatment (C) are classical characteristics of apoptosis and not necrosis.

Mentions: Apparent alterations in cell morphology and detachment from the culture surface were observed after 48 h of treatment with 125 μM Sulindac Sulfide and 500 μM Exisulind in both cell lines, when cells became sparse and rounded (Fig. 4b). Cell shrinkage, nuclear condensation and formation of apoptotic bodies were visible on propidium iodide labeled cell nuclei, which are classical characteristics of apoptosis and not necrosis (Fig. 4c).


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)

Changes in cell morphology characteristic for apoptosis Morphologic changes became evident after 48 h of treatment with 500 μM Exisulind or 125 μM Sulindac Sulfide. A-C: Phase contrast photomicrographs of S462 cells before (A) and after Exisulind (B) treatment. Cell shrinkage, nuclear condensation and formation of apoptotic bodies shown on immunocytochemically labeled cell nuclei with PI after Sulindac Sulfide treatment (C) are classical characteristics of apoptosis and not necrosis.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Changes in cell morphology characteristic for apoptosis Morphologic changes became evident after 48 h of treatment with 500 μM Exisulind or 125 μM Sulindac Sulfide. A-C: Phase contrast photomicrographs of S462 cells before (A) and after Exisulind (B) treatment. Cell shrinkage, nuclear condensation and formation of apoptotic bodies shown on immunocytochemically labeled cell nuclei with PI after Sulindac Sulfide treatment (C) are classical characteristics of apoptosis and not necrosis.
Mentions: Apparent alterations in cell morphology and detachment from the culture surface were observed after 48 h of treatment with 125 μM Sulindac Sulfide and 500 μM Exisulind in both cell lines, when cells became sparse and rounded (Fig. 4b). Cell shrinkage, nuclear condensation and formation of apoptotic bodies were visible on propidium iodide labeled cell nuclei, which are classical characteristics of apoptosis and not necrosis (Fig. 4c).

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