Antimalarial drug together with anticancer drug is efficient against leukemia
Combination of approved drugs offers new strategies for acute myeloid leukemia
The combined use of two well-known active substances can fight leukemic cells and limit their spread. This is the result of a study conducted by the Karl Landsteiner University of Health Sciences (KL Krems) and recently published in the journal cancer Letters. In experiments, the researchers discovered that an established antimalarial drug in combination with a proven anticancer drug influences the activity of a specific transcription factor and thus inhibits the expansion and spread of leukemia cells. The combination not only killed the leukemia cells, but also significantly reduced their infiltration into the bone marrow.
Acute myeloid leukemia (AML) is an aggressive form of blood cancer in which immature white blood cells proliferate in the bone marrow and interfere with normal blood cell formation. The protein STAT3 is often overactive in these cells. Attempts to inhibit its activity therapeutically have – so far – not been very successful. The research team led by Prof. Dr. Dagmar Stoiber-Sakaguchi, head of the Division of Pharmacology at the KL Krems, has now investigated a new strategy.
Tiny Shifts. Big Impact.
STAT3 exists in two isoforms: STAT3α and STAT3β. While the α form promotes the expansion of cancer cells, the β form has an inhibitory effect. Previous work by Prof. Stoiber-Sakaguchi showed that a low ratio of STAT3β to STAT3α is associated with a poorer prognosis in AML patients. „We therefore looked for ways to shift this ratio in a way that would provide therapeutic benefit,“ explains Prof. Stoiber-Sakaguchi, who is also the last author of the study. „And we succeeded.“
The study focused on the combination of the antimalarial drug atovaquone, which has already shown anticancer properties, with the anticancer drug selinexor. „We were able to demonstrate that this combination changes the STAT3 isoform ratio in favor of the β-form under experimental conditions,“ explains Stefanie Weiss, first author of the study and a doctoral student at the Medical University of Vienna. „In addition, the AML cells were killed and their presence in the bone marrow was significantly reduced”.
More Adhesion. Less Spread
The team also observed an increased production of the protein CD62L. CD62L is an adhesion molecule on the surface of AML cells whose expression is up-regulated by STAT3β. „We suspect that increased expression of the adhesion molecule CD62L leads to a delay in the spread of leukemia cells and thus, as shown in animal models, significantly prolongs survival,“ explains Prof. Stoiber-Sakaguchi.
In summary, this work opens a new avenue for utilizing cancer therapeutics targeting the STAT3 protein. Previous approaches to inhibit STAT3 did not achieve the desired effect because they did not consider that STAT3 exists in two variants – encoded by the same gene but transcribed differently. The KL Krems team now proposes to focus on the ratio of STAT3β to STAT3α and to specifically influence it. At least experimentally, they achieved an anti-cancer effect by combining two already approved and established substances.
Original publication
Atovaquone and selinexor as a novel combination treatment option in acute myeloid leukemia. S. Weiss, B. Zdársky, A. Witalisz-Siepracka, S. Edtmayer, A. Holzer, K. Heindl, E. Casanova, K. Podar & D. Stoiber. Cancer Letters 613 (2025)
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