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Credit: Robert Paulson
Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).
NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).
In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.
The researchers detailed these results in Cancer Research.
“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.
Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.
To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.
The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.
On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.
Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.
“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark. 
Credit: Robert Paulson
Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).
NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).
In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.
The researchers detailed these results in Cancer Research.
“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.
Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.
To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.
The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.
On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.
Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.
“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.
Credit: Robert Paulson
Preclinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs) might help prevent relapse in acute myeloid leukemia (AML).
NSAIDs inhibit 5-lipoxygenase (5-LO), and researchers found this enzyme plays a key role in the survival of leukemic stem cells (LSCs).
In cell cultures and mouse models of AML, NSAIDs selectively and efficiently attacked LSCs.
The researchers detailed these results in Cancer Research.
“These results provide the basis for the potential implementation of 5-LO-inhibitors as stem cell therapeutic agents for a sustained AML cure, although this must be investigated further in preclinical and clinical studies,” said study author Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany.
Recent research suggested 5-LO is critical to the maintenance of LSCs in chronic myeloid leukemia. So Dr Ruthardt and his colleagues hypothesized that 5-LO might be a therapeutic target for AML.
To test that theory, the researchers inhibited 5-LO in a PML/RARα -positive model of AML. As LSC models, the team used Sca-1+/lin- murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.
The group found that inhibiting 5-LO with the NSAIDs CJ-13,610 and zileuton reduced the stem cell capacity of PML/RARα-expressing HSPCs. The NSAIDs also inhibited Wnt signaling.
On the other hand, targeted genetic inhibition of 5-LO did not recapitulate the NSAIDs’ effects on leukemogenic potential and the aberrant stem cell capacity induced by PML/RARα.
Further investigation revealed that Wnt and LSC inhibition is mediated by the enzymatically inactive form of 5-LO, which hinders the nuclear translocation of ß-catenin. So it seems 5-LO inhibitors also inhibit Wnt signaling due to the generation of a catalytically inactive form of 5-LO, which assumes a new function.
“[T]here are plans for further molecular biological studies with the objective of understanding exactly how the 5-LO inhibitors act on the leukemic cells,” said study author Thorsten J. Maier, MD, PhD, of Aarhus University in Denmark.