Mitochondrial complex I inhibition by homoharringtonine: A novel strategy for suppression of chronic myeloid leukemia.

Abstract

Chronic myeloid leukemia (CML) is a hematologic malignancy predominantly driven by the BCR-ABL fusion gene. One of the significant challenges in treating CML lies in the emergence of resistance to tyrosine kinase inhibitors (TKIs), especially those associated with the T315I mutation. Homoharringtonine (HHT) is an FDA-approved, naturally-derived drug with known anti-leukemic properties, but its precise mechanisms of action remain incompletely understood. In this study, we rigorously evaluated the anti-CML activity of HHT through both in vitro and in vivo assays, observing substantial anti-CML effects. To elucidate the molecular mechanisms underpinning these effects, we performed proteomic analysis on BCR-ABL T315I mutation-bearing cells treated with HHT. Comprehensive pathway enrichment analysis identified oxidative phosphorylation (OXPHOS) as the most significantly disrupted, suggesting a key role in the mechanism of action of HHT. Further bioinformatics exploration revealed a substantial downregulation of proteins localized within mitochondrial complex I (MCI), a critical OXPHOS component. These results were validated through Western blot analysis and were supplemented by marked reductions in MCI activity, ATP level, and oxygen consumption rate (OCR) upon HHT exposure. Collectively, our results shed light on the potent anti-CML properties of HHT, particularly its effectiveness against T315I mutant cells through MCI inhibition. Our study underscores a novel therapeutic strategy to overcome BCR-ABL T315I mutation resistance, illuminating a previously uncharted mechanism of action for HHT.

• Authors: Han Han, Chen Zhao, Mengchen Liu, Hongxuan Zhu, Fancheng Meng, Ying Zhang, Guibin Wang, Li Wang, Lijun Di, Simon Mingyuen Lee, Qingwen Zhang, Guozhen Cui
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 218 Pg. 115875 (12 2023) ISSN: 1873-2968 [Electronic] England
• PMID: 37871881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023. Published by Elsevier Inc.

Chemical References

• Homoharringtonine
• Fusion Proteins, bcr-abl
• Protein Kinase Inhibitors

Topics

• Humans
• Homoharringtonine (pharmacology)
• Proteomics
• Cell Proliferation
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (metabolism)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Mutation