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Blood, 26 February 2009, Vol. 113, No. 9, pp. 2014-2021.
Prepublished online as a Blood First Edition Paper on October 31, 2008; DOI 10.1182/blood-2008-05-157842.
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Submitted May 20, 2008
Accepted October 4, 2008
Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells
Esther Hulleman, Karin M. Kazemier, Amy Holleman, David J. VanderWeele, Charles M. Rudin, Mathilde J. C. Broekhuis, William E. Evans, Rob Pieters, and Monique L. Den Boer*
Department of Pediatric Oncology and Hematology, ErasmusMC - Sophia Children's Hospital, University Medical Center, Rotterdam, Netherlands
Department of Oncology, Sidney Kimmel Comprehensive Cander Center, Johns Hopkins University, Baltimore, MD, United States
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, United States
* Corresponding author; email: m.l.denboer{at}erasmusmc.nl.
Treatment failure in pediatric acute lymphoblastic leukemia (ALL) is related to cellular resistance to glucocorticoids (e.g. prednisolone). Recently, we demonstrated that genes associated with glucose metabolism are differentially expressed between prednisolone-sensitive and -resistant precursor B-lineage leukemic patients. Here, we show that prednisolone resistance is associated with an 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) or 3-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 cytotoxicity. This sensitizing effect of the glycolysis inhibitors in glucocorticoid resistant ALL cells was not found for other classes of antileukemic drugs (i.e., vincristine and daunorubicin). Moreover, downregulation of the expression of GAPDH by RNA interference also sensitized to prednisolone, comparable to 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.
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