Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells
Treatment failure in pediatric acute lymphoblastic leukemia (ALL) is related to cellular resistance to glucocorticoids (eg, prednisolone). Recently, we demonstrated that genes associated with glucose metabolism are differentially expressed between prednisolone-sensitive and prednisolone-resistant precursor B-lineage leukemic patients. Here, we show that prednisolone resistance is associated with increased glucose consumption and that inhibition of glycolysis sensitizes prednisolone-resistant ALL cell lines to glucocorticoids. Treatment of prednisolone-resistant Jurkat and Molt4 cells with 2-deoxy-D-glucose (2-DG), lonidamine (LND), or3-bromopyruvate (3-BrPA) increased the in vitro sensitivity to glucocorticoids, while treatment of the prednisolone-sensitive cell lines Tom-1 and RS4; 11 did not influence drug cyto-toxicity. This sensitizing effect of the glycolysis inhibitors in glucocorticoid-resistant ALL cells was not found for other classes of antileukemic drugs (ie, vincris-tine and daunorubicin). Moreover, down-regulation of the expression of GAPDH by RNA interference also sensitized to prednisolone, comparable with treatment with glycolytic inhibitors. Importantly, the ability of 2-DG to reverse glucocorticoid resistance was not limited to cell lines, but was also observed in isolated primary ALL cells from patients. Together, these findings indicate the importance of the glycolytic pathway in glucocorticoid resistance in ALL and suggest that targeting glycolysis is a viable strategy for modulating prednisolone resistance in ALL.
|Keywords||RNA, RNA interference, acute lymphocytic leukemia, article, asparaginase, bromopyruvic acid, cancer cell culture, cell isolation, comparative study, controlled study, daunorubicin, deoxyglucose, down regulation, drug sensitivity, glucocorticoid, glucose, glucose intake, glyceraldehyde 3 phosphate dehydrogenase, glycolysis, human, human cell, in vitro study, leukemia cell, leukemia cell line, lonidamine, modulation, prednisolone, priority journal, protein expression, pyruvic acid derivative, unclassified drug, vincristine|
|Persistent URL||dx.doi.org/10.1182/blood-2008-05-157842, hdl.handle.net/1765/18242|
Hulleman, E, Kazemier, K.M, Holleman, A, VanderWeele, D.J, Rudin, C.M, Broekhuis, M.J.C, … den Boer, M.L. (2009). Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood, 113(9), 2014–2021. doi:10.1182/blood-2008-05-157842