Inhibiting the enzyme 5-lipoxygenase (5-LO) can eradicate cancer stem cell-like cells (CSCs) in acute myeloid leukemia (AML), according to a preclinical study
published in Cancer Research.
Previous research suggested the enzyme is needed to maintain CSCs in chronic myeloid leukemia.
So investigators theorized that 5-LO could be a therapeutic target for AML, as CSCs are thought to cause the spread and relapse of this disease.
To test that theory, the team evaluated the effects of 5-LO inhibition in a PML/RARα-positive model of AML. As a model of CSCs, they used Sca-1+/lin− murine hematopoietic stem and progenitor cells (HSPCs), which were retrovirally transduced with PML/RARα.
The researchers targeted 5-LO genetically and pharmacologically. And they found that 5-LO inhibition interfered with the aberrant stem cell capacity of PML/RARα-expressing HSPCs.
Inhibiting 5-LO also inhibited Wnt signaling, which has been shown to be critical for CSC maintenance.
Additional investigation revealed that inhibition of Wnt signaling and CSCs was due to the generation of a catalytically inactive form of 5-LO, which hindered nuclear translocation of β-catenin.
Considering these results together, as well as evidence that CSCs mediate AML relapse, the investigators concluded that eradicating CSCs via 5-LO inhibition may offer a new treatment approach for AML.
“These results form the basis for a possible use of the 5-lipoxygenase inhibitors as stem cell therapy for a sustainable cure for acute myeloid leukemia,” said Martin Ruthardt, MD, of Goethe University in Frankfurt, Germany. “But this must firstly be studied further in preclinical and clinical studies in humans.”
“We are now in the process of examining the molecular mechanism in more detail in order to find out how the inhibitors precisely work on the leukemia stem cells,” added Thorsten Jürgen Maier, MD, PhD, of Goethe University and Aarhus University in Denmark. “We very much hope that our results will be of benefit for leukemia patients.”
