Drug Information

Drug (ID: DG02151) and It's Reported Resistant Information

• Name: ATO-Digoxin
• Synonyms: ATO-Digoxin
• Indication:
  In total 1 Indication(s)
  . .; .; [1]

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute myeloid leukemia [ICD-11: 2A60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NFE2-related factor 2 (NRF2) [1]

• Sensitive Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Oxidative stress response signaling pathway; Regulation; N.A.
• In Vivo Model: MV4-11 ATO-R C6 xenograft mice; Mus musculus
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: In-vivo drug treatment assay
• Mechanism Description: We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

References

• Ref 1: Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia. Ann Hematol. 2024 Jun;103(6):1919-1929.