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

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.

 

Comments:

That's an incredibly detailed and informative summary of a study on HHT's potential in treating CML, especially in cases with the T315I mutation. It's fascinating how the study combined in vitro and in vivo assays, proteomic analysis, and pathway enrichment to unravel the mechanisms behind HHT's effectiveness.

The discovery that HHT disrupts oxidative phosphorylation (OXPHOS), particularly targeting mitochondrial complex I (MCI), is significant. This insight into its mode of action could pave the way for novel therapeutic strategies to combat resistance associated with the BCR-ABL T315I mutation.

It seems like your study is contributing not just to understanding HHT's efficacy against CML but also to identifying potential vulnerabilities in the T315I mutation that could be exploited for therapeutic purposes. It's exciting to see research shedding light on uncharted mechanisms of action for existing drugs, potentially opening new avenues for targeted therapies.

Is there anything specific you're exploring further based on these findings? Perhaps diving deeper into the downstream effects of MCI inhibition or potential combination therapies with HHT to enhance its efficacy against CML?

Related Products

Cat.No.	Product Name	Information
S9063	Harringtonine	Harringtonine is a natural cephalotaxine alkaloid that inhibits protein biosynthesis. It also exhibits antiviral and anticancer activities.

Related Targets

Antiviral