Premium
Bioenergetic modulation overcomes glucocorticoid resistance in T‐lineage acute lymphoblastic leukaemia
Author(s) -
Samuels Amy L.,
Heng Jasmin Y.,
Beesley Alex H.,
Kees Ursula R.
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12727
Subject(s) - glycolysis , oxidative phosphorylation , oligomycin , anaerobic glycolysis , biology , bioenergetics , cancer research , pharmacology , drug resistance , glucocorticoid , immunology , endocrinology , metabolism , biochemistry , atpase , mitochondrion , enzyme , genetics
Summary Drug‐resistant forms of acute lymphoblastic leukaemia ( ALL ) are a leading cause of death from disease in children. Up to 25% of patients with T‐cell ALL (T‐ ALL ) develop resistance to chemotherapeutic agents, particularly to glucocorticoids ( GC s), a class of drug to which resistance is one of the strongest indicators of poor clinical outcome. Despite their clinical importance, the molecular mechanisms that underpin GC resistance and leukaemia relapse are not well understood. Recently, we demonstrated that GC ‐resistance is associated with a proliferative metabolism involving the up‐regulation of glycolysis, oxidative phosphorylation and cholesterol biosynthesis. Here we confirm that resistance is directly associated with a glycolytic phenotype and show that GC ‐resistant T‐ ALL cells are able to shift between glucose bioenergetic pathways. We evaluated the potential for targeting these pathways in vitro using a glycolysis inhibitor, 2‐deoxyglucose (2 DG ), and the oxidative phosphorylation inhibitor oligomycin in combination with methylprednisolone ( MPRED ). We found that oligomycin synergized with MPRED to sensitize cells otherwise resistant to GC s. Similarly we observed synergy between MPRED and simvastatin, an inhibitor of cholesterol metabolism. Collectively, our findings suggest that dual targeting of bioenergetic pathways in combination with GC s may offer a promising therapeutic strategy to overcome drug resistance in ALL .