A specific group of antihistamine medications can eradicate leukaemic stem cells, according to research from the Leukaemic Stem Cell research group of the Josep Carreras Leukaemia Research Institute. Led by Ruth M. Risueño, this group has found that a class of antihistamines can selectively kill these malignant stem cells while sparing healthy cells. Their work was published on August 28 in EBioMedicine.
The Leukaemic Stem Cell group investigates acute myeloid leukaemia (AML) and the cells associated with the spreading, persisting, and reappearance of the disease. AML is a form of leukaemia with a particularly poor prognosis, with the 5-year survival rate for AML patients 20 and older being about 24%. For those younger than 20, the survival rate is 67%. It is estimated that 21,450 people will receive an AML diagnosis in the U.S. this year, making the disease the second most common leukaemia amongst adults and children. 10,920 deaths from AML are expected to occur this year, with a majority occurring in adults.
The leukaemia stem cells can be differentiated, replicating themselves indefinitely to uphold a population. When these cells differentiate, they yield all types of mature leukaemic cells found in a tumor. These adult cells are more sensitive to chemotherapy, but their precursor stem cells are responsible for the disease progression. To eradicate these stem cells, they can be killed or induced to differentiate into mature cells.
“If we can differentiate all leukaemic stem cells, this population would be depleted,” explained Risueño. “Therefore, its ability to maintain the disease and the chances of regeneration and relapse would be lost.”
In collaboration with Dr. Josep M Cornet-Masana, Risueño conducted the first phase of an in silico search and screening of molecules using computer procedures. In doing so, they identified a group of antihistamines that could potentially be used to treat AML. Experimenting with these antihistamines in mouse models, the researchers found that these drugs were able to induce differentiation of the stem cells. In addition, these antihistamines entered the cell’s mitochondria and lysosomes, inducing failure and eventually cell death.
“This does not affect healthy cells because the process of transforming leukaemic cells implies that mitochondria and lysosomes are more fragile,” explained Risueño. “This fact allows them to have more resistance to pre-apoptotic stimuli, that is, to the cell’s safety mechanisms that cause their death when something goes wrong, and increase the metabolic rate, which is necessary for all tumor cells. What is an advantage for the propagation of the tumor becomes a disadvantage for its protection against such drugs.”
These antihistamines cannot currently be used to combat leukaemia due to how quickly they degrade in the body and the lack of a direct administration method on cancer cells. This research team is currently working to make these antihistamines more stable and to develop a mechanism that allows them to introduce these drugs directly to the stem cells of interest.
Funding for this research was provided by the Mutua Madrileña Foundation, the Josep Carreras International Foundation, the Obra Social la Caixa and the Generalitat de Catalunya through its CERCA program.
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