The Antifungal That Sneaked Into Leukemia's Power Room

[Lights up on a tiny bone marrow workshop, where perfectly respectable blood cells are trying to do their jobs while a gang of leukemia cells keeps stealing the extension cords.]

Acute myeloid leukemia, or AML, is a cancer of immature blood-forming cells. Instead of growing up into useful white blood cells, some cells get stuck in a reckless teenager phase: multiplying, crowding the bone marrow, and refusing to clean their room. Treatment can knock AML back, sometimes very hard. The trouble is that a small group of stubborn cells often survives. These are leukemia stem cells, and they can help the disease return like weeds after you only clipped the tops.

That is where this new study in Blood gets rather clever. Himonas and colleagues went hunting for old drugs that might have a new job: cutting off the energy supply that AML cells, especially resistant ones, seem to rely on. Their surprise candidate was itraconazole, a medicine doctors already use to treat fungal infections.¹ Yes, an antifungal. Science is occasionally like opening a toolbox and discovering your soup ladle also fixes the lawn mower.

The Little Power Plants With Big Attitudes

Cells make usable energy in a few ways, but one major route is oxidative phosphorylation, mercifully shortened to OXPHOS. Think of OXPHOS as the mitochondrial power station. Nutrients go in, electrons get passed along a chain of molecular machinery, and the cell gets ATP, the tiny energy coin of biology.

AML has a complicated relationship with this power station. Many leukemia cells, and especially leukemia stem cells, lean heavily on mitochondrial metabolism and OXPHOS for survival.²³ That makes OXPHOS tempting as a target. But there is a catch, because of course there is. Normal cells need mitochondria too. You cannot simply unplug every power station in the body unless your medical plan was written by a toaster.

Previous OXPHOS inhibitors have run into problems: not strong enough, too toxic, or not practical enough for real patients.⁴ So the question becomes: can researchers find a drug that hits leukemia's energy habits in a more useful way?

A Drug Screen With a Good Nose

The researchers used a metabolism-specific drug-repurposing screen. In plain English, they tested existing drugs under conditions designed to reveal whether a compound was messing with mitochondrial energy production. It is a bit like checking which appliance trips the breaker by turning them on one at a time, except the appliances are cancer cells and the breaker is cellular respiration.

Itraconazole stood out. The team found that it inhibited OXPHOS in AML cells, including by disrupting activity in the tricarboxylic acid cycle, also called the TCA cycle, and the electron transport chain. More specifically, the drug interfered with complex I, a major entry point where electrons from NADH join the mitochondrial assembly line.¹

The study also tied this effect to CYP51A1, the classic target of azole antifungals. In fungi, itraconazole blocks ergosterol production, which fungi need for their cell membranes. In AML cells, this work suggests CYP51A1 also has a role in mitochondrial respiration and complex I activity. That is a tidy little plot twist: the same drug target that annoys fungi may also expose a metabolic weak spot in leukemia cells.

To check the mechanism, the scientists used a yeast enzyme called NDI1, which can bypass parts of complex I-related NADH oxidation. When AML cells expressed NDI1, some mitochondrial function came back after itraconazole treatment.¹ That is the biology version of saying, "Aha, the problem really was in this part of the wiring."

Why Cytarabine Needed a Kitchen Helper

Cytarabine is a standard chemotherapy drug in AML. It can kill dividing leukemia cells, but leukemia stem cells can be maddeningly good at lying low, like socks that vanish in the laundry and reappear only when you have company.

In this study, itraconazole worked best as a partner. In patient-derived AML cells and mouse xenograft models, itraconazole plus cytarabine targeted therapy-resistant leukemia stem cells more effectively than cytarabine alone.¹ That matters because relapse is often driven by cells that survive initial treatment. If chemotherapy is water on the garden path, a metabolism-targeting add-on might be the soap that helps loosen the grime.

This also fits with a larger body of AML research showing that resistant leukemia cells can shift their metabolism, including toward mitochondrial respiration and fatty acid use.⁵ Cancer cells are not just "fast-growing." They are adaptable. They switch snacks, change routes, and hide in the bone marrow neighborhood like they know all the back alleys.

The Sensible Bit Before Anyone Raids the Medicine Cabinet

Itraconazole is already FDA-approved, which makes it attractive for repurposing. Existing drugs come with known dosing, safety history, and pharmacy logistics. That can shorten the road from lab idea to clinical testing.

But this is not a permission slip to self-medicate. Itraconazole can interact with many drugs, including through CYP3A4 and P-glycoprotein pathways, and AML treatment is already a delicate balancing act.⁶ The current evidence here is preclinical. The next grown-up step is carefully designed clinical trials to see whether this combination is safe, tolerable, and effective in people with AML.

Still, the idea is a good one: do not just swing harder at leukemia. Study what keeps the hard-to-kill cells alive, then take away their lunch money. Politely, scientifically, and with institutional review board approval.

References

Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.