Crucial for chronic lymphocytic leukaemia (CLL) development and progression are the iterative cycles of cell re-activation and proliferation that take place in lymphoid tissues. These iterative cycles are fundamental for the development and the progression of the disease. Since cellular fatty acid (FA) import and oxidation (FAO) were recently reported to be upregulated in CLL, compared to normal B lymphocytes, we explored the in vitro effects of ST1326, a reversible inhibitor of carnitine-palmitoyl transferase 1A (CPT1A), on leukaemic cells subject to activating microenvironment-mimicking stimuli. ST1326 induced dose-dependent mitochondrial dysfunction and cell death, which were remarkably higher in activated/proliferating than quiescent CLL cells. Drug sensitivity was observed irrespective of the presence of TP53 alterations or chromosomal abnormalities, which are known to cause chemoresistance in CLL patients. The treatment of normal B lymphocytes with ST1326, at doses lethal to CLL cells, causes only a slight inhibition of cell activation/proliferation, indicating a modest cytostatic, not cytotoxic, effect. ST1326 cytotoxicity in CLL was associated with decreased levels of intracellular Acetyl-CoA and down-regulation of signalling pathways that are crucial for leukaemic cell survival, activation and proliferation. In particular, environment-induced activation of STAT3 and STAT6 transcription factors, known to upregulate anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-xL, was impaired by ST1326. As a consequence, drug combination experiments with the BH3-mimetic ABT-199/Venetoclax, whose effects are counteracted by Mcl-1/Bcl-xL and cell proliferation, showed strong ST1326-mediated potentiation of ABT-199 cytotoxicity in activated/proliferating CLL cells. We also observed that ST1326 showed a synergic effect with Fludarabine in activated/proliferating CLL cells. The data indicate that CLL cells turning to an activated/proliferating state become more dependent on FAO and more sensitive to FAO-antagonists, and pave the way for ST1326 as an adjuvant tool in anti-CLL drug-combination regimens with drugs that lose efficacy on proliferating leukaemic cells.
|Titolo della tesi:||A reversible carnitine palmitoyltransferase 1 (CPT1) inhibitor offsets chronic lymphocytic leukaemia cell proliferation|
|Data di discussione:||18-apr-2019|
|Appare nelle tipologie:||Tesi di dottorato|