Oncotarget

Research Papers:

Shift in energy metabolism caused by glucocorticoids enhances the effect of cytotoxic anti-cancer drugs against acute lymphoblastic leukemia cells

Shigeki Aoki _, Michie Morita, Takuya Hirao, Masashi Yamaguchi, Reika Shiratori, Megumi Kikuya, Hiroji Chibana and Kousei Ito

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Oncotarget. 2017; 8:94271-94285. https://doi.org/10.18632/oncotarget.21689

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Abstract

Shigeki Aoki1,*, Michie Morita1,*, Takuya Hirao1, Masashi Yamaguchi2, Reika Shiratori1, Megumi Kikuya1, Hiroji Chibana2 and Kousei Ito1

1Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba-city, Chiba 260-8675, Japan

2Medical Mycology Research Center, Chiba University, Chiba-city, Chiba 260-8673, Japan

*These authors have contributed equally to this work

Correspondence to:

Shigeki Aoki, email: aokishigeki@chiba-u.jp

Keywords: ALL, autophagy, glucocorticoids, glycolysis, oxidative phosphorylation

Received: June 16, 2017    Accepted: September 21, 2017    Published: October 09, 2017

ABSTRACT

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Treatments include glucocorticoids (GCs) such as dexamethasone (Dex) and prednisolone, which may be of value when used alongside cytotoxic anti-cancer drugs. To predict therapeutic efficacy of GCs, their activity against ALL cells is usually examined prior to chemotherapy; however, few studies have examined their effects when used in combination with other drugs. The paradox is that cytotoxic anti-cancer drugs that are effective against proliferating cancer cells show synergistic effects when used with GCs that prevent cell proliferation. To address this point, we investigated intracellular energy metabolism in ALL CCRF-CEM cell clones classified according to their sensitivity to Dex and cytotoxic anti-cancer drugs in bulk cultures of mixed cells. We found that Dex suppressed glycolysis, the most important metabolic system in cancer cells, in cells that were damaged by etoposide (a cytotoxic anti-cancer drug), and the cells showed a concomitant increase in mitochondrial oxidative phosphorylation. Furthermore, autophagy, an intracellular bulk degradation system, regulated mitochondrial viability. We also found that mitochondria, whose function is enhanced by Dex, were susceptible to anti-cancer drugs that inhibit respiratory complexes (e.g., etoposide and daunorubicin), resulting in increased production of reactive oxygen species and subsequent cytotoxicity. Taken together, the present study points the way toward a more accurate prediction of the sensitivity of ALL cells to the combined action of anti-cancer drugs and GCs, by taking into consideration the shift in intracellular energy metabolism caused by GCs: namely, from glycolysis to mitochondrial oxidative phosphorylation mediated by autophagy.


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