Bithionol eliminates acute myeloid leukaemia stem-like cells by suppressing NF-κB signalling and inducing oxidative stress, leading to apoptosis and ferroptosis.
Ingrid R S B DiasRafaela G A CostaAna Carolina B da C RodriguesSuellen L R SilvaMaiara de S OliveiraMilena B P SoaresRosane B DiasLudmila F ValverdeClarissa A Gurgel RochaLauren V CairnsKen I MillsDaniel Pereira BezerraPublished in: Cell death discovery (2024)
Acute myeloid leukaemia (AML) is a lethal bone marrow neoplasm caused by genetic alterations in blood cell progenitors. Leukaemic stem cells (LSCs) are responsible for the development of AML, drug resistance and relapse. Bithionol is an old anthelmintic drug with potential antibacterial, antiviral, antifungal, anti-Alzheimer, and antitumour properties. In this work, we focused on the anti-AML LSC properties of bithionol. This compound inhibited the viability of both solid and haematological cancer cells, suppressed AML stem-like cells, and inhibited AML growth in NSG mice at a dosage of 50 mg/kg, with tolerable systemic toxicity. Bithionol significantly reduced the levels of phospho-NF-κB p65 (Ser529) and phospho-NF-κB p65 (Ser536) and nuclear NF-κB p65 translocation in AML cells, indicating that this molecule can suppress NF-κB signalling. DNA fragmentation, nuclear condensation, cell shrinkage, phosphatidylserine externalisation, loss of transmembrane mitochondrial potential, caspase-3 activation and PARP-(Asp 214) cleavage were detected in bithionol-treated AML cells, indicating the induction of apoptosis. Furthermore, this compound increased mitochondrial superoxide levels, and bithionol-induced cell death was partially prevented by cotreatment with the selective ferroptosis inhibitor ferrostatin-1, indicating the induction of ferroptosis. In addition, bithionol synergised with venetoclax in AML cells, indicating the translational potential of bithionol to enhance the effects of venetoclax in patients with AML. Taken together, these data indicate that bithionol is a potential new anti-AML drug.
Keyphrases
- acute myeloid leukemia
- oxidative stress
- cell death
- cell cycle arrest
- induced apoptosis
- pi k akt
- signaling pathway
- allogeneic hematopoietic stem cell transplantation
- bone marrow
- stem cells
- diabetic rats
- endoplasmic reticulum stress
- dna damage
- lps induced
- drug induced
- nuclear factor
- mesenchymal stem cells
- single cell
- acute lymphoblastic leukemia
- cell therapy
- metabolic syndrome
- gene expression
- ischemia reperfusion injury
- human health
- risk assessment
- dendritic cells
- liver failure
- cognitive decline
- insulin resistance
- cell free
- skeletal muscle
- immune response
- electronic health record
- climate change
- heat shock
- data analysis
- single molecule
- hydrogen peroxide
- candida albicans
- acute respiratory distress syndrome
- low grade
- circulating tumor