Abstract
Chronic myeloid leukemia (CML) is an oncogenic hematologic disorder defined by the BCR-ABL1 fusion gene, which initiates pathological proliferation of myeloid lineage cells. While tyrosine kinase inhibitors (TKIs) have substantially improved clinical outcomes, therapeutic resistance associated with the T315I mutation continues to present a significant obstacle. This research evaluates the efficacy of caffeic acid phenethyl ester (CAPE), a bioactive natural product, in countering TKI resistance mediated by this specific genetic alteration. The investigation employed a comprehensive methodology including MTT assay, apoptotic analysis through flow cytometry, proteomic profiling, and bioinformatic interrogation to characterize CAPE’s effects on both wild-type and T315I-mutant CML cellular models. MTT assay indicated that CAPE exhibited potent anti-metabolic activity against CML cells, promoting apoptosis in a dose-dependent manner. Proteomic analysis identified a marked effect of CAPE on the oxidative phosphorylation(OXPHOS) pathway, particularly through the inhibition of mitochondrial complex I(MCI) activity. This inhibition may disrupt cellular energy metabolism, potentially reducing ATP production and heightening susceptibility to cell death. Our findings indicate that CAPE could serve as an adjunctive therapy for CML against drug resistance caused by the T315I mutation through a mechanism that does not directly inhibit BCR-ABL1. This study underscores the promise of targeting mitochondrial metabolism as a novel approach for overcoming therapeutic resistance in CML.
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The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors gratefully acknowledge the Dink Laboratory at the Jinan University School of Pharmacy for generously providing the cell lines utilized in this investigation.
Funding
This work was supported by funding from the Guangdong Province Administration of Chinese Medicine Research Project (Grant No. 20221330) and the Futian Healthcare Research Project (Grant Nos. FTWS2022027, FTWS2022059, FTWS2023071).
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Conceptualization, Meng Li and Dongxue Liu; Methodology, Meng Li and Zhiwei Zhang; Software, Zhiwei Zhang; Validation, Meng Li, Dongxue Liu, and Biqian Fu; Formal Analysis, Meng Li and Zhihua Peng; Investigation, Meng Li, Dongxue Liu, Han Han and Ying Zhang; Resources, Han Han, Ying Zhang and Ruihua Xiong; Data Curation, Meng Li and Biqian Fu; Writing – Original Draft Preparation, Meng Li; Writing – Review & Editing, Meng Li, Dongxue Liu, Zhiwei Zhang, Biqian Fu, Ruihua Xiong, and Yanli Fu; Visualization, Zhiwei Zhang; Supervision, Yuhe Lei; Project Administration, Yanli Fu; Funding Acquisition, Yanli Fu.
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This research was funded by the Shenzhen Association of Chinese Medicine (Grant No. 2024140 F) and the Futian Healthcare Research Project (Grant Nos. FTWS2022027, FTWS2022059, FTWS2023071).
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Li, M., Liu, D., Zhang, Z. et al. Caffeic acid phenethyl ester induced apoptosis in chronic myeloid leukemia cells by inhibiting mitochondrial complex I. Sci Rep (2026). https://doi.org/10.1038/s41598-025-34553-8
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DOI: https://doi.org/10.1038/s41598-025-34553-8
