# Implementation of Natural Products and Derivatives in Acute Myeloid Leukemia Management: Current Treatments, Clinical Trials and Future Directions

## TL;DR

This review explores how natural products and their derivatives are used in treating acute myeloid leukemia, highlighting current therapies and future research directions.

## Contribution

The paper provides a comprehensive overview of natural products and derivatives currently approved or in trials for AML treatment.

## Key findings

- Natural products and derivatives like cytarabine and midostaurin are FDA-approved for AML treatment.
- Novel natural products are being tested in preclinical and clinical trials to target AML pathways.
- AML treatment remains challenging due to disease heterogeneity and multidrug resistance.

## Abstract

Acute myeloid leukemia (AML) is a clonal hematologic disorder marked by clinical and biological heterogeneity. Natural products (NPs) derived from plants, animals and microorganisms, have been used as healing agents for thousands of years and still today continue to be the most important source of new potential therapeutic agents. To date, several bioactive NPs and semi-synthetic products, such as cytarabine, anthracyclines, midostaurin and melphalan, are currently approved for the treatment of AML. As the treatment of AML remains an ongoing medical challenge, novel NPs and derivatives targeting tumor-related processes have entered preclinical and clinical trials for AML. This review provides a comprehensive summary of NPs and their derivatives approved for the treatment of AML, as well as those which exhibit potential therapeutic abilities for treating AML.

Bioactive natural products (NPs) may play a critical role in cancer progression by targeting nucleic acids and a wide array of proteins, including enzymes. Furthermore, a large number of derivatives (NPDs), including semi-synthetic products and pharmacophores from NPs, have been developed to enhance the solubility and stability of NPs. Acute myeloid leukemia (AML) is a poor-prognosis hematologic malignancy characterized by the clonal accumulation in the blood and bone marrow of myeloid progenitors with high proliferative capacity, survival and propagation abilities. A number of potential pathways and targets have been identified for development in AML, and include, but are not limited to, Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenases resulting from genetic mutations, BCL2 family members, various signaling kinases and histone deacetylases, as well as tumor-associated antigens (such as CD13, CD33, P-gp). By targeting nucleic acids, FLT3 or CD33, several FDA-approved NPs and NPDs (i.e., cytarabine, anthracyclines, midostaurin, melphalan and calicheamicin linked to anti-CD33) are the major agents of upfront treatment of AML. However, the effective treatment of the disease remains challenging, in part due to the heterogeneity of the disease but also to the involvement of the bone marrow microenvironment and the immune system in favoring leukemic stem cell persistence. This review summarizes the current state of the art, and provides a summary of selected NPs/NPDs which are either entering or have been investigated in preclinical and clinical trials, alone or in combination with current chemotherapy. With multifaceted actions, these biomolecules may target all hallmarks of AML, including multidrug resistance and deregulated metabolism.