A new study has shed light on the process leukemia cells use to evade apoptosis and revealed drugs that can fight this process.
Investigators found that leukemia cells expel a molecule that starts apoptosis, but antimalarial drugs and antifungal drugs can halt this process and force the leukemia cells to self-destruct.
Alexandre Chigaev, PhD, of the University of New Mexico in Albuquerque, and his colleagues described these discoveries in Oncotarget.
The investigators theorized that leukemia cells might evade death by regulating 3’-5’-cyclic adenosine monophosphate (cAMP), which is associated with pro-apoptotic signaling.
The team thought leukemic cells might possess mechanisms that efflux cAMP from the cytoplasm, thereby protecting them from apoptosis.
In studying VLA-4—an adhesion molecule that keeps each cell in its niche—the investigators discovered that cAMP reduces VLA-4’s adhesive properties, allowing cells to detach.
“That’s how we stumbled upon it,” Dr Chigaev said. “Cyclic AMP reduces cell adhesion, and maybe that’s one of the mechanisms by which [leukemic] cells leave bone marrow niches.”
The investigators then confirmed that cAMP starts apoptosis in leukemia cells. And they showed that leukemia cells could efflux cAMP, but normal blood cells could not.
The team substantiated their findings by testing several drugs that block cAMP efflux.
The drugs, which are all approved by the US Food and Drug Administration, are used to fight malaria or fungal infections. They include artesunate, dihydroartemisinin, clioquinol, cryptotanshinone, parthenolide, and patulin.
The investigators found these drugs successfully decreased cAMP efflux and induced apoptosis in a model of acute myeloid leukemia, in B-lineage acute lymphoblastic leukemia cell lines, and in samples from patients with B-lineage acute lymphoblastic leukemia.
On the other hand, the drugs did not affect peripheral blood mononuclear cells.
“This particular mechanism of action has not been reported for these drugs,” Dr Chigaev said. “And the idea that cells can have this apoptotic escape, or apoptotic evasion, through cyclic AMP pumping, that’s new. It’s never been reported previously.”
Dr Chigaev and his colleagues noted that repurposing already-approved drugs could greatly shorten the approval process to use them for leukemia.
Since the drugs were tested on cells from leukemia patients, the team hopes to continue seeing promising results. They have begun animal studies in preparation for clinical trials.
