Stable isotope tracing reveals glucose metabolism characteristics of drug-resistant B-cell acute lymphoblastic leukemia.

Zhengwei Duan, Pengfei Guo, Yang Chen, Mengyao Wang, Rong Hu, Mengting Liu, Yaoxin Zhang, Yanxi Lu, Yuhan Qian, Enjie Wei, Jianghua Feng

Journal: Analytica chimica acta 2025;1352():343884

PMID: 40210293

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Adult B-cell acute lymphocytic leukemia (B-ALL) is a malignant hematologic tumor characterized by the uncontrolled proliferation of B-cell lymphoblasts in the bone marrow. Despite advances in treatment, including chemotherapy and consolidation therapy, many B-ALL patients experience unfavorable prognoses due to the development of drug resistance. The precise mechanisms governing chemotherapy resistance, particularly those related to metabolic reprogramming within tumors, remain inadequately elucidated.

RESULTS

Nalm6/DOX cells exhibited significantly elevated levels of glucose, pyruvate, alanine, glutamine, and glycine compared to Nalm6 cells. Conversely, reduced levels of citrate, acetate, and leucine were observed in Nalm6/DOX cells. Upon exposure to the culture medium supplemented with tracer C-glucose, the Nalm6/DOX cells showed an increase in the abundance of C-alanine and a decrease in the levels of C-lactate, indicating impaired utilization of C-pyruvate. Combining β-chloro-alanine (ALTi) with DOX could decrease the drug resistance phenotype of Nalm6/DOX cells. The results demonstrated that glycolysis and tricarboxylic acid cycle were suppressed in Nalm6/DOX cells, while metabolic flux through the alanine and glutamine pathways was increased. Therefore, inhibition of alanine biosynthesis in Nalm6/DOX exhibits the potential to reverse drug resistance.

SIGNIFICANCE

A new insight into the impact of metabolism on chemotherapy resistance in B-ALL has been gained through the use of stable isotope resolved metabolomics based on nuclear magnetic resonance and ultra-performance liquid chromatography/tandem mass spectrometry. This provides promising ways for the development of innovative therapeutic strategies to alleviate drug resistance and relapse in affected patients.

Address: Department of Laboratory Medicine, Fujian Medical University, Fuzhou, 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fujian Medical University, Fuzhou, 350122, China; Institute of Precision Medicine, Fujian Medical University, Fuzhou, 350004, China.; Department of Laboratory Medicine, Fujian Medical University, Fuzhou, 350122, China; Department of Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.; Department of Laboratory Medicine, Fujian Medical University, Fuzhou, 350122, China.; Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, 361005, China.; Department of Laboratory Medicine, Fujian Medical University, Fuzhou, 350122, China; Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fujian Medical University, Fuzhou, 350122, China; Institute of Precision Medicine, Fujian Medical University, Fuzhou, 350004, China. Electronic address: [email protected].

DOI: 10.1016/j.aca.2025.343884

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MeSH Terms: Humans, Drug Resistance, Neoplasm, Glucose, Carbon Isotopes, Cell Line, Tumor, Doxorubicin, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Isotope Labeling, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma