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


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


Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells - Download this document for free, or read online. Document in PDF available to download.

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

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





Author: Zheng Li 1, Jian-Ru Guo 1, Qian-Qian Chen 1, Cai-Yun Wang 1, Wei-Jia Zhang 2, Mei-Cun Yao 2 and Wei Zhang 1,*

Source: http://mdpi.com/



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