Tenofovir Alafenamide Promotes Differentiation and Induces Apoptosis of AML Cells by Inhibiting Telomerase Reverse Transcriptase.

BACKGROUND/AIM: Acute myeloid leukemia (AML) is the most common type of leukemia in adults. However, patient prognosis remains poor despite advances in our understanding of its molecular cytogenetics and pathogenesis. Differentiation therapy aims to overcome the characteristic differentiation blockade observed in leukemia cells, but its efficacy is limited to specific AML subtypes. Therefore, there is an urgent need to develop novel therapeutic agents for AML.

MATERIALS AND

METHODS

To identify potential therapeutic candidates, we screened 100 US Food and Drug Administration-approved drugs by measuring CD11b expression. The anti-leukemia effects of tenofovir alafenamide (TAF) were evaluated using flow cytometry, MTS assays, cell proliferation assays, and trypan blue staining in U937 and THP-1 AML cells. Real-time polymerase chain reaction was performed to assess the expression of differentiation-associated genes and relative telomere length. Western blotting was used to detect proteins involved in the DNA-damage response.

RESULTS

Through chemical screening, TAF was identified as a drug with significant differentiation-inducing activity in AML cells. TAF promoted differentiation while simultaneously reducing cell viability and inhibiting cell proliferation. Moreover, TAF exhibited synergistic effects when combined with cytarabine. TAF also suppressed cell proliferation in primary AML patient samples harboring various mutations. Mechanistically, TAF inhibited telomerase reverse transcriptase activity and increased generation of reactive oxygen species, thereby activating the DNA-damage response.

CONCLUSION

TAF may serve as a promising novel therapeutic agent for the treatment of AML.