Exploring the Antitumor Mechanism of High-Dose Cytarabine through the Metabolic Perturbations of Ribonucleotide and Deoxyribonucleotide in Human Promyelocytic Leukemia HL-60 Cells.
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.
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. lizhengcpu@163.com.
Zheng
Z
Li
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. guojianrumust@gmail.com.
Jian-Ru
JR
Guo
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. qqchen@must.edu.mo.
Qian-Qian
QQ
Chen
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. Cywang@must.edu.mo.
Cai-Yun
CY
Wang
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guang Zhou 510006, China. vega0313@126.com.
Wei-Jia
WJ
Zhang
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guang Zhou 510006, China. yaomeicun@gmail.com.
Mei-Cun
MC
Yao
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. wzhang@must.edu.mo.
Wei
W
Zhang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000032:analysis*; D008401:Gas Chromatography-Mass Spectrometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D012265:Ribonucleotides / Q000032:analysis*
D000964:Antimetabolites, Antineoplastic; D003854:Deoxyribonucleotides; D012265:Ribonucleotides; D003561:Cytarabine; D055372:AMP-Activated Protein Kinases
LC-MS; deoxyribonucleotide; high-dose Ara-C; mechanism; perturbation; ribonucleotide