Bioenergetic modulation overcomes glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia.
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 (GCs), 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 (2DG), and the oxidative phosphorylation inhibitor oligomycin in combination with methylprednisolone (MPRED). We found that oligomycin synergized with MPRED to sensitize cells otherwise resistant to GCs. 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 GCs may offer a promising therapeutic strategy to overcome drug resistance in ALL.
Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, WA, Australia.
Amy L
AL
Samuels
Jasmin Y
JY
Heng
Alex H
AH
Beesley
Ursula R
UR
Kees
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005690:Galactose / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008775:Methylprednisolone / Q000494:pharmacology / Q000627:therapeutic use; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D005938:Glucocorticoids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009840:Oligomycins; D005690:Galactose; D008775:Methylprednisolone
acute lymphoblastic leukaemia; glucocorticoid; glycolysis; metabolism; resistance