07 March 2022

Scientists are investigating the possibility of altering an enzyme that provides energy to acute myeloid leukaemia (AML) cells.

Dr Jérôme Tamburini of Inserm and the University of Paris, France, and colleagues explain that AML has a poor prognosis, “particularly among the elderly, in whom age and comorbidities preclude the use of intensive therapies”.

“Novel therapeutic approaches for AML are therefore critically needed,” they add.

The researchers have focused on an enzyme called AMPK, which regulates the cell's energy production. Activation of AMPK increases natural cell death, called apoptosis, by triggering the stress response in cells. Previous lab tests of AMPK activators have shown anti-cancer activity. So, in the current study, the team used a direct AMPK activator called GSK621 on AML cells.

They found that this approach killed AML cells “by rewiring mitochondrial metabolism that primes mitochondria to apoptosis”.

Dr Tamburini says: “AMPK is the main detector of the cell's energy level. This pathway is activated when energy is lacking and initiates the degradation of certain nutrients to produce the necessary energy - a process called catabolism. Without energy, no cell can survive.”

He adds that activating AMPK using GSK621 “sensitises the cells to the effects of another pharmacological drug, venetoclax, which is now widely used to treat acute myeloid leukaemia, although with limited effectiveness when used alone.”

When both drugs were given to mice, they controlled tumour growth much more effectively than either drug given alone.

Dr Tamburini concludes: “We will now be able to review all the drugs known to have an effect on these pathways and determine which combinations would be the most effective.”

Source: Grenier A, Poulain L, Mondesir J, Jacquel A, Bosc C, Stuani L, Mouche S, Larrue C, Sahal A, Birsen R, Ghesquier V, Decroocq J, Mazed F, Lambert M, Andrianteranagna M, Viollet B, Auberger P, Lane AA, Sujobert P, Bouscary D, Sarry JE, Tamburini J. (2022) “AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia.” Cell Reports, doi: 10.1016/j.celrep.2021.110197

Link: https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01701-0

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