Antitumor effect and nanoparticle development of the Adamantyl Retinoid ST1926 in acute myeloid leukemia -

Abstract

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disorder of hematopoietic progenitor cells, which have lost their normal ability to differentiate. AML represents one of the most complex types of leukemias. Clinical treatment of AML subtypes is highly dependent on the patients’ karyotype. Until today, there is no standard regimen to treat AML patients.Retinoids regulate a wide range of biological processes, including development, differentiation, proliferation, and cell death, especially in hematopoietic cells. Differentiation therapy using the natural retinoid all-trans retinoic acid (ATRA) became the paradigm for the treatment of acute promyelocytic leukemia (APL), an AML subtype. However, in non-APL AML patients, ATRA is only effective on those presenting with nucleophosmin-1 mutations, and was often linked with acquired resistance and disease relapse. Therefore, synthetic retinoids, specifically the adamantyl ST1926, emerged as potent anticancer agent. However, ST1926 development in clinic was limited due to its rapid glucuroconjugation resulting in low plasma concentrations. Nanomedicine has recently gained widespread attention, where it enables more efficient drug delivery, increasing stability, bioavailability, and reducing drug toxicity. Therefore, we aimed at investigating the antitumor effect of ST1926 using human non-APL AML in vitro models, developing nanoparticle formulations of the drug, and reproducing an AML xenograft mouse models for preclinical drug assessment.We used representative human non-APL AML cell lines harboring different genetic mutations and representing several AML karyotypes. We showed that sub-micromolar concentrations of ST1926 inhibited the proliferation of all tested AML cell lines and primary AML patient cells in an irreversible manner. ST1926 induced apoptosis as evidenced by the accumulation of treated cells in the preG1 region of the cell cycle, Annexin V positivity, PARP cleavage, and mitochondrial membrane dissipation. Furthermore