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Molecules 2017, 22(3), 499; doi:10.3390/molecules22030499

Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells

1
State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China
2
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guang Zhou 510006, China
*
Author to whom correspondence should be addressed.
Academic Editor: Suzanne Peyrottes
Received: 8 March 2017 / Revised: 17 March 2017 / Accepted: 20 March 2017 / Published: 21 March 2017
(This article belongs to the Special Issue Nucleoside and Nucleotide Analogues)
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Abstract

Despite the apparent clinical benefits of high-dose cytarabine (Ara-C) over lower dose Ara-C in acute myeloid leukemia (AML) therapy, the mechanism behind high-dose Ara-C therapy remains uncertain. In this study, a LC-MS-based method was carried out to investigate the metabolic alteration of ribonucleotide and deoxyribonucleotide in human promyelocytic leukemia cells (HL-60) after treatment with Ara-C to reveal its antitumor mechanism. The metabolic results revealed that four nucleotides (ATP, ADP, CDP, and dCTP) could be used as potential biomarkers indicating the benefit of high-dose Ara-C over lower dose Ara-C treatment. Combining metabolic perturbation and cell cycle analysis, we conjectured that, apart from the acknowledged mechanism of Ara-C on tumor inhibition, high-dose Ara-C could present a specific action pathway. It was suggested that the pronounced rise in AMP/ATP ratio induced by high-dose Ara-C can trigger AMP-activated protein kinase (AMPK) and subsequently Forkhead Box, class O (FoxO), to promote cell cycle arrest. Moreover, the significant decrease in CDP pool induced by high-dose Ara-C might further accelerate the reduction of dCTP, which then aggravates DNA synthesis disturbance. As a result, all of these alterations led to heightened tumor inhibition. This study provides new insight in the investigation of potential mechanisms in the clinical benefits of high-dose Ara-C in therapy for AML. View Full-Text
Keywords: high-dose Ara-C; mechanism; LC-MS; ribonucleotide; deoxyribonucleotide; perturbation high-dose Ara-C; mechanism; LC-MS; ribonucleotide; deoxyribonucleotide; perturbation
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MDPI and ACS Style

Li, Z.; Guo, J.-R.; Chen, Q.-Q.; Wang, C.-Y.; Zhang, W.-J.; Yao, M.-C.; Zhang, W. Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells. Molecules 2017, 22, 499.

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