Limits...
Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα.

Steinert G, Oancea C, Roos J, Hagemeyer H, Maier T, Ruthardt M, Puccetti E - PLoS ONE (2011)

Bottom Line: Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific.Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling.We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Goethe-University, Frankfurt, Germany.

ABSTRACT
Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARα-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.

Show MeSH

Related in: MedlinePlus

Induction of apoptosis in patient-derived NB4 cells by Sulindac derivatives.Rate of apoptosis in patient-derived PML/RARα-positive NB4 cells was assessed by 7AAD staining upon exposure to clinically achievable concentrations (50–150 µM) of SSi and SSo. Apoptosis was measured after 72 h. Data are expressed as the mean of three independent experiments with standard deviation (SD). Statistical analysis was performed using Student's t-test (* - p<0.05; ** - p<0.01).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3139642&req=5

pone-0022540-g002: Induction of apoptosis in patient-derived NB4 cells by Sulindac derivatives.Rate of apoptosis in patient-derived PML/RARα-positive NB4 cells was assessed by 7AAD staining upon exposure to clinically achievable concentrations (50–150 µM) of SSi and SSo. Apoptosis was measured after 72 h. Data are expressed as the mean of three independent experiments with standard deviation (SD). Statistical analysis was performed using Student's t-test (* - p<0.05; ** - p<0.01).

Mentions: The maximum plasma concentrations after either SSo or SSi oral administration to patients were 100 µM and 50–100 µM, respectively [21], [34], [35]. To examine clinical doses of SSo and SSi, we compared the capacity of these compounds to induce apoptosis in NB4 cells at concentrations between 0 and 150 µM. As shown in Figure 2, SSi induced physiologically relevant rates of apoptosis within clinically achievable concentrations, between 75 and 100 µM, whereas 100 µM SSo induced only very limited apoptosis. Based on these data, all subsequent studies were performed using SSi.


Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARα and PLZF/RARα.

Steinert G, Oancea C, Roos J, Hagemeyer H, Maier T, Ruthardt M, Puccetti E - PLoS ONE (2011)

Induction of apoptosis in patient-derived NB4 cells by Sulindac derivatives.Rate of apoptosis in patient-derived PML/RARα-positive NB4 cells was assessed by 7AAD staining upon exposure to clinically achievable concentrations (50–150 µM) of SSi and SSo. Apoptosis was measured after 72 h. Data are expressed as the mean of three independent experiments with standard deviation (SD). Statistical analysis was performed using Student's t-test (* - p<0.05; ** - p<0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3139642&req=5

pone-0022540-g002: Induction of apoptosis in patient-derived NB4 cells by Sulindac derivatives.Rate of apoptosis in patient-derived PML/RARα-positive NB4 cells was assessed by 7AAD staining upon exposure to clinically achievable concentrations (50–150 µM) of SSi and SSo. Apoptosis was measured after 72 h. Data are expressed as the mean of three independent experiments with standard deviation (SD). Statistical analysis was performed using Student's t-test (* - p<0.05; ** - p<0.01).
Mentions: The maximum plasma concentrations after either SSo or SSi oral administration to patients were 100 µM and 50–100 µM, respectively [21], [34], [35]. To examine clinical doses of SSo and SSi, we compared the capacity of these compounds to induce apoptosis in NB4 cells at concentrations between 0 and 150 µM. As shown in Figure 2, SSi induced physiologically relevant rates of apoptosis within clinically achievable concentrations, between 75 and 100 µM, whereas 100 µM SSo induced only very limited apoptosis. Based on these data, all subsequent studies were performed using SSi.

Bottom Line: Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific.Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling.We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Goethe-University, Frankfurt, Germany.

ABSTRACT
Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARα, PLZF/RARα, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARα and PLZF/RARα or AML-1/ETO activate Wnt signaling by upregulating γ-catenin and β-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARα-positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both β-catenin and γ-catenin in X-RARα-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARα-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARα, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings.

Show MeSH
Related in: MedlinePlus