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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

Correlation of growth inhibition (reduction of viable cell number) and apoptosis The increase of apoptotic cells is paralleled by reduction of viable cell number at the corresponding concentrations. A-B: Viability of cell lines S462 and S520 were measured by their ability to reduce XTT metabolically to a purple formazan product after 48 h of treatment with Exisulind and Sulindac Sulfide at different concentrations. The percentage of viable cells was determined setting the absorbance of cells treated with the vehicle as 100%. C-D: Percentages of apoptotic cells were determined by photometric quantification of DNA- and histone-fragmentation after 48 h of drug treatment. The absorbance mean values of treated samples (triplicates) were normalized to the corresponding control of untreated cells and the maximal absorbance from the test compound included in the assay was used as positive control (100% apoptosis).
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Figure 2: Correlation of growth inhibition (reduction of viable cell number) and apoptosis The increase of apoptotic cells is paralleled by reduction of viable cell number at the corresponding concentrations. A-B: Viability of cell lines S462 and S520 were measured by their ability to reduce XTT metabolically to a purple formazan product after 48 h of treatment with Exisulind and Sulindac Sulfide at different concentrations. The percentage of viable cells was determined setting the absorbance of cells treated with the vehicle as 100%. C-D: Percentages of apoptotic cells were determined by photometric quantification of DNA- and histone-fragmentation after 48 h of drug treatment. The absorbance mean values of treated samples (triplicates) were normalized to the corresponding control of untreated cells and the maximal absorbance from the test compound included in the assay was used as positive control (100% apoptosis).

Mentions: To determine the relation between growth inhibition and apoptosis, we measured the number of viable cells and the amount of DNA-fragmentation simultaneously. The viability of the cells decreased drastically after 48 h of drug treatment (Fig. 2a,2b). At the highest applied concentrations of Exisulind and Sulindac Sulfide, only 1–33% of the cells were actively metabolizing compared to cells treated with the vehicle alone. As shown in figures 2c,2d, the reduction of viable cell number is paralleled by the increase of apoptosis rates up to 25–45% for 500 μM Exisulind and up to 43–60% for 125 μM Sulindac Sulfide, determined by photometrical quantification of DNA-fragmentation. Supplementation of DMSO to the culture medium at concentrations used for drug treatment had no effect on cell death.


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)

Correlation of growth inhibition (reduction of viable cell number) and apoptosis The increase of apoptotic cells is paralleled by reduction of viable cell number at the corresponding concentrations. A-B: Viability of cell lines S462 and S520 were measured by their ability to reduce XTT metabolically to a purple formazan product after 48 h of treatment with Exisulind and Sulindac Sulfide at different concentrations. The percentage of viable cells was determined setting the absorbance of cells treated with the vehicle as 100%. C-D: Percentages of apoptotic cells were determined by photometric quantification of DNA- and histone-fragmentation after 48 h of drug treatment. The absorbance mean values of treated samples (triplicates) were normalized to the corresponding control of untreated cells and the maximal absorbance from the test compound included in the assay was used as positive control (100% apoptosis).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC425591&req=5

Figure 2: Correlation of growth inhibition (reduction of viable cell number) and apoptosis The increase of apoptotic cells is paralleled by reduction of viable cell number at the corresponding concentrations. A-B: Viability of cell lines S462 and S520 were measured by their ability to reduce XTT metabolically to a purple formazan product after 48 h of treatment with Exisulind and Sulindac Sulfide at different concentrations. The percentage of viable cells was determined setting the absorbance of cells treated with the vehicle as 100%. C-D: Percentages of apoptotic cells were determined by photometric quantification of DNA- and histone-fragmentation after 48 h of drug treatment. The absorbance mean values of treated samples (triplicates) were normalized to the corresponding control of untreated cells and the maximal absorbance from the test compound included in the assay was used as positive control (100% apoptosis).
Mentions: To determine the relation between growth inhibition and apoptosis, we measured the number of viable cells and the amount of DNA-fragmentation simultaneously. The viability of the cells decreased drastically after 48 h of drug treatment (Fig. 2a,2b). At the highest applied concentrations of Exisulind and Sulindac Sulfide, only 1–33% of the cells were actively metabolizing compared to cells treated with the vehicle alone. As shown in figures 2c,2d, the reduction of viable cell number is paralleled by the increase of apoptosis rates up to 25–45% for 500 μM Exisulind and up to 43–60% for 125 μM Sulindac Sulfide, determined by photometrical quantification of DNA-fragmentation. Supplementation of DMSO to the culture medium at concentrations used for drug treatment had no effect on cell death.

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