Acute myeloidleukemia is the most prevalent type of acute Leukemia among adults.

Recent research has changed the properties of a natural substance so that it could be used to treat Acute Myeloid Leukemia.

Recent research led by Gonçalo Bernardes, group leader at the Instituto de Medicina Molecular João Lobo Antunes (iMM; Portugal) and Professor at the University of Cambridge (Cambridge, UK), and Gonzalo Jiménez-Osés, group leader at the Center for Cooperative Research in Biosciences (Derio, Spain), and published in the scientific journal Nature Chemistry reports the development of new chemistry on natural compounds derived from Brazilian lapacho tree bark to obtain a therapeutic agent that could be efficient to treat acute myeloid leukemia.

Acute myeloid leukemia is the most common type of acute leukemia among adults. It is an aggressive form of cancer that occurs when there is an abnormal increase in the number of certain types of immature cells. These cells are called myeloid cells. Five years later, the survival rate of patients is just 20 percent. Relapses from disease are very common.

“It’s important to find new therapeutic strategies for acute myeloid leukemia. There are a lot of natural compounds with medicinal value that can’t be used as therapies at the moment due to toxicity and negative effects on healthy cells. In our work, which was done in collaboration with Gonzalo Jiménez-Osés, we used these natural compounds and modified them in a way that controls their negative effects and allows us to take advantage of their therapeutic value”, explains Gonçalo Bernardes, group leader at iMM and co-leader of the study.

Gonçalo Bernardes, Principal Investigator at iMM and co-leader of the study. Credit: Gonçalo Ribeiro, iMM

Back in 2018, this team used machine learning to identify the targeting site of a compound from the lapacho tree bark that belongs to the family of ortho-quinones, called β-lapachone. These compounds are well-suited for treating leukemia as they are known to be able to reduce cancerous cells’ abnormal growth.

“The compound that we explored in this study, called β-lapachone, is a promising drug to treat leukemia, but its reactive properties could have undesirable effects. Two strategies were combined to minimize the negative side effects of the compound. We added a chemical element to the compound that protects against its reactive properties. This chemical group acts as a mask to reduce the drug’s toxicity. This mask is released in an acidic environment that corresponds to cells’ interior. This is the second strategy. We attached the modified compound to a protein, an antibody, that delivers it directly to the interior of cancer cells.”, adds Gonçalo Bernardes.

“Cancer cells have certain marks that tell them apart from healthy cells. We know that acute myeloid leukemia has one of these markers, CD33. Our natural product was attached to an antibody that specifically binds to CD33. This allows the drug’s passage through the body without causing any harm to healthy cells. When the antibody meets the cancer cell, the CD33 marker is bound and the drug is delivered. At this moment it will turn into its active and toxic form, killing the cancer cell”, clarifies Ana Guerreiro, co-second author of the study.

The therapeutic value of this approach to the treatment of acute lymphoblastic leukemia is well-known. However, this chemistry can also be applied to other valuable natural compounds. This allows the use of compounds that have therapeutic potential and are not suitable for medicinal purposes.

Reference: “Controlled masking and targeted release of redox-cycling ortho-quinones via a C–C bond-cleaving 1,6-elimination” by Lavinia Dunsmore, Claudio D. Navo, Julie Becher, Enrique Gil de Montes, Ana Guerreiro, Emily Hoyt, Libby Brown, Viviane Zelenay, Sigitas Mikutis, Jonathan Cooper, Isaia Barbieri, Stefanie Lawrinowitz, Elise Siouve, Esther Martin, Pedro R. Ruivo, Tiago Rodrigues, Filipa P. da Cruz, Oliver Werz, George Vassiliou, Peter Ravn, Gonzalo Jiménez-Osés, and Gonçalo J. L. Bernardes, 27 June 2022, Nature Chemistry.
DOI: 10.1038/s41557-022-00964-7

This work was created at the University of Cambridge in the UK with researchers from iMM in Portugal in collaboration the Center for Cooperative Research in Biosciences in Spain, AstraZeneca in the UK, Friedrich Schiller University Jena in Germany and the Basque Foundation for Science in Spain.

The study was funded by the European Union’s Horizon 2020 research and innovation program, Agencia Estatal Investigacion of Spain, Severo Ochoa Excellence Accreditation, Cancer Research UK, and the Deutsche Forschungsgemeinschaft.

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