ArticleJournal of experimental & clinical cancer research : CR2025
Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Cholesterol Reprogramming in Acute Myeloid Leukemia: Integrating Tumor-Intrinsic Metabolism and Immune Crosstalk.Diseases (Basel, Switzerland) · 2026Review
- Review
- Heat shock protein 60-targeted peptide-conjugated platinum nanozyme: redox regulation by multi-enzyme activities induces mitochondrial reprogramming and acute leukemia cells fate switch.Journal of nanobiotechnology · 2026Article
- Biomimetic Copper-Doped Nano-Aluminum Adjuvant Potentiates Therapy in Chemoresistant Acute Myeloid Leukemia.Advanced healthcare materials · 2026Article
- OPA1 as a Cancer Target: Molecular Mechanisms, Structural Insights, and Strategies for Drug Development.Antioxidants (Basel, Switzerland) · 2026Review
- Inhibiting TRIM21 Neddylation Rejuvenates Oocyte Quality in PCOS by Regulating Ubiquitination of CPT1A.Research (Washington, D.C.) · 2026Article
- Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.PLoS biology · 2025Article
- The Pathophysiological Role of Mitochondrial Oxidative Stress in Rheumatic Diseases.Journal of inflammation research · 2025Review
- Mitochondrial dynamics in cisplatin resistance: molecular mechanisms and therapeutic targeting.Frontiers in oncology · 2025Review
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Authors and funding
13 authors.
Funding
Abstract
backgroundAcute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.
methodThis study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.
resultsTMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.
conclusionTMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.
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