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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

TUNEL assay of cell line S462 showing time dependent induction of apoptosis Cells were either treated with 0.2% DMSO for 48 h (A, D), 500 μM Exisulind (Exi) for 24 h (B) and 48 h (C) or 125 μM Sulindac Sulfide (s. s.) for 24 h (E) and 48 h (F). The percentage of gated cells (upper box) represents the ratio of apoptotic cells (FITC-BrdU) to the total number of cells (PI), values are presented beneath each display.
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Figure 3: TUNEL assay of cell line S462 showing time dependent induction of apoptosis Cells were either treated with 0.2% DMSO for 48 h (A, D), 500 μM Exisulind (Exi) for 24 h (B) and 48 h (C) or 125 μM Sulindac Sulfide (s. s.) for 24 h (E) and 48 h (F). The percentage of gated cells (upper box) represents the ratio of apoptotic cells (FITC-BrdU) to the total number of cells (PI), values are presented beneath each display.

Mentions: Apoptosis induction by Sulindac metabolites was further examined by TUNEL assay on both cell lines. Figure 3 displays a time dependent induction of apoptosis in MPNST cell line S462 treated with 500 μM Exisulind and 125 μM Sulindac Sulfide. In both cell lines, the apoptosis rate increased 3–5 fold after 24 h treatment with Exisulind in comparison to untreated cells, and 7–21 fold after 48 h treatment. Similarly, 24 h treatment with Sulindac Sulfide caused a 3–4 fold increase in the proportion of apoptotic cells, and a 10–27 fold increase after 48 h treatment (Table 1).


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)

TUNEL assay of cell line S462 showing time dependent induction of apoptosis Cells were either treated with 0.2% DMSO for 48 h (A, D), 500 μM Exisulind (Exi) for 24 h (B) and 48 h (C) or 125 μM Sulindac Sulfide (s. s.) for 24 h (E) and 48 h (F). The percentage of gated cells (upper box) represents the ratio of apoptotic cells (FITC-BrdU) to the total number of cells (PI), values are presented beneath each display.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: TUNEL assay of cell line S462 showing time dependent induction of apoptosis Cells were either treated with 0.2% DMSO for 48 h (A, D), 500 μM Exisulind (Exi) for 24 h (B) and 48 h (C) or 125 μM Sulindac Sulfide (s. s.) for 24 h (E) and 48 h (F). The percentage of gated cells (upper box) represents the ratio of apoptotic cells (FITC-BrdU) to the total number of cells (PI), values are presented beneath each display.
Mentions: Apoptosis induction by Sulindac metabolites was further examined by TUNEL assay on both cell lines. Figure 3 displays a time dependent induction of apoptosis in MPNST cell line S462 treated with 500 μM Exisulind and 125 μM Sulindac Sulfide. In both cell lines, the apoptosis rate increased 3–5 fold after 24 h treatment with Exisulind in comparison to untreated cells, and 7–21 fold after 48 h treatment. Similarly, 24 h treatment with Sulindac Sulfide caused a 3–4 fold increase in the proportion of apoptotic cells, and a 10–27 fold increase after 48 h treatment (Table 1).

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