Chlorinated adenosine analogue induces AMPK and autophagy in chronic lymphocytic leukaemia cells during therapy.
Christine M StellrechtLisa S ChenMary L AyresJennifer B DennisonShujun ShentuYuling ChenMichael J KeatingWilliam G WierdaVarsha GandhiPublished in: British journal of haematology (2017)
8-chloro-adenosine (8-Cl-Ado) is currently in phase-I clinical trials for acute myeloid leukaemia and chronic lymphocytic leukaemia (CLL). Previously, we demonstrated that treatment with 8-Cl-Ado leads to diminished ATP levels. We hypothesized that AMP-activated protein kinase (AMPK) signalling would be initiated in these cells, leading to induction of autophagy. AMPK activation and induction of autophagy were demonstrated during preclinical incubations in CLL cells with the analogues. Importantly, we extended similar observations in CLL lymphocytes during an 8-Cl-Ado phase-I trial. In conclusion, 8-Cl-Ado treatment induces autophagy in CLL lymphocytes in vitro as well as in vivo during clinical trial.
Keyphrases
- protein kinase
- induced apoptosis
- clinical trial
- endoplasmic reticulum stress
- cell death
- cell cycle arrest
- signaling pathway
- oxidative stress
- skeletal muscle
- chronic lymphocytic leukemia
- phase ii
- study protocol
- acute myeloid leukemia
- stem cells
- immune response
- drug induced
- peripheral blood
- mass spectrometry
- open label
- mesenchymal stem cells
- respiratory failure
- acute respiratory distress syndrome
- cell therapy
- molecular dynamics simulations
- replacement therapy