NOVEL POTENTIAL HDAC INHIBITOR INDUCES CELL DIFFERENTIATION IN ACUTE MYELOID LEUKEMIA CELLS

Abstract

Objective: Histone deacetylases (HDAC) are enzymes responsible for the deacetylation of histone proteins and play important roles in cell survival, cell proliferation, and gene expression in various types of cancers, including leukemias. High HDAC levels have been observed in hematological neoplasm patients being associated with poor prognosis. In a previous study, we identified three purine-derived phenylhydroxamate as potential HDAC inhibitors with selective potential antineoplastic effects in hematological neoplasms. The present study aimed to evaluate the effects of compound 82, the most potent purine-derived phenylhydroxamate identified, on cell differentiation of acute myeloid leukemia cells. Material and methods: NB4-R2 (resistant to ATRA) and THP-1 leukemia cell lines were used. Vorinostat was used as a reference drug. Compound 82, a purine-derived phenylhydroxamate with potential HDAC inhibitor activity, was used. Cells were exposed for 96h to the vehicle or the drugs. Cell differentiation was evaluated by CD11b staining and flow cytometry, and morphological analysis by cytospin and panoptic staining. Statistical analysis was performed by ANOVA and Bonferroni post-test. A p < 0.05 was considered significant. Results: NB4-R2 and THP-1 cells treated with vorinostat or compound 82 presented increased markers of differentiation (CD11b) (p < 0.05). A reduction in the nucleus-to-cytoplasm ratio and increases in vacuolization were observed upon 96h of exposition to drugs. Discussion and Conclusion: Therapy based on cell differentiation has been successfully applied to some types of acute leukemias, such as acute promyelocytic leukemia. Thus, the identification of new compounds with the potential to induce differentiation is of interest in oncohematology. Our results indicate that purine-derived phenylhydroxamate induced cell differentiation in acute leukemia cell lines. Funding: Supported by CNPq, CAPES, and FAPESP.