2-Deoxy-D-glucose cooperates with arsenic trioxide to induce apoptosis in leukemia cells: involvement of IGF-1R-regulated Akt/mTOR, MEK/ERK and LKB-1/AMPK signaling pathways.

Abstract

While the anti-tumor efficacy of 2-deoxy-D-glucose (2-DG) is normally low in monotherapy, it may represent a valuable radio- and chemo-sensitizing agent. We here demonstrate that 2-10 mM 2-DG cooperates with arsenic trioxide (ATO) and other antitumor drugs to induce apoptosis in human myeloid leukemia cell lines. Using ATO and HL60 as drug and cell models, respectively, we observed that 2-DG/ATO combination activates the mitochondrial apoptotic pathway, as indicated by Bid-, and Bax-regulated cytochrome c and Omi/HtrA2 release, XIAP down-regulation, and caspase-9/-3 pathway activation. 2-DG neither causes oxidative stress nor increases ATO uptake, but causes inner mitochondria membrane permeabilization as well as moderate ATP depletion, which nevertheless do not satisfactorily explain the pro-apoptotic response. Surprisingly 2-DG causes cell line-specific decrease in LKB-1/AMPK phosphorylation/activation, and also causes Akt/mTOR/p70S6K and MEK/ERK activation, which is prevented by co-treatment with ATO. The use of kinase-specific pharmacologic inhibitors and/or siRNAs reveals that apoptosis is facilitated by AMPK inactivation and restrained by Akt and ERK activation, and that Akt and ERK activation mediates AMPK inhibition. Finally, 2-DG stimulates IGF-1R phosphorylation/activation, and co-treatment with IGF-1R inhibitor prevents 2-DG effects on Akt, ERK and AMPK, and facilitates 2-DG-provoked apoptosis. In summary 2-DG elicits IGF-1R-mediated AMPK inactivation and Akt and ERK activation, which facilitates or restrain apoptosis, respectively. 2-DG-provoked AMPK inactivation increases the apoptotic efficacy of ATO, while in turn ATO-provoked Akt and ERK inactivation may increase the efficacy of 2-DG as anti-tumor drug.

• Authors: María Cristina Estañ, Eva Calviño, Elena de Blas, María del Carmen Boyano-Adánez, Maria Luz Mena, Milagros Gómez-Gómez, Eduardo Rial, Patricio Aller
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 84 Issue 12 Pg. 1604-16 (Dec 15 2012) ISSN: 1873-2968 [Electronic] England
• PMID: 23041229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Arsenicals
• Oxides
• Protein Kinase Inhibitors
• Adenosine Triphosphate
• Deoxyglucose
• Protein Kinases
• MTOR protein, human
• Receptor, IGF Type 1
• TOR Serine-Threonine Kinases
• Arsenic Trioxide

Topics

• Adenosine Triphosphate (metabolism)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Cell Division (drug effects)
• Cell Line, Tumor
• Deoxyglucose (pharmacology)
• Humans
• Leukemia (enzymology, metabolism, pathology)
• Mitochondria (drug effects)
• Oxidative Stress
• Oxides (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Receptor, IGF Type 1 (antagonists & inhibitors, physiology)
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases (metabolism)