Mitochondria-targeted propranolol conjugate PL37 induces mitophagy, potently suppressing hemangioma growth in xenograft models
Background
Infantile hemangioma (IH) is a common benign tumor, with propranolol as the first-line treatment. However, its clinical utility is hampered by systemic adverse effects, variable patient responses, and an incompletely understood mechanism of action. Current treatments often lack specificity, leading to off-target effects. This study aims to develop a more effective and mechanism-driven therapeutic strategy by targeting mitochondria, a key organelle in cell proliferation and survival, to overcome propranolol's limitations and improve IH therapy.
Study Design
Researchers designed and synthesized a series of propranolol-peptide conjugates, focusing on mitochondria-targeted derivatives. They evaluated PL37 in vitro using human umbilical vein endothelial cells (HUVECs) and hemangioma-derived endothelial cells, assessing proliferation, migration, invasion, tube formation, and apoptosis. Mechanistic studies involved measuring reactive oxygen species (ROS) generation, mitochondrial membrane potential, and structural integrity. In vivo, PL37 was tested in a hemangioma xenograft model to assess tumor growth, angiogenesis, and systemic toxicity.
Results
In vitro, PL37 potently inhibited endothelial cell proliferation, migration, invasion, and tube formation. It significantly induced apoptosis in both HUVECs and hemangioma-derived endothelial cells. Mechanistically, PL37 triggered severe mitochondrial dysfunction, characterized by excessive reactive oxygen species (ROS) generation, collapse of mitochondrial membrane potential, and structural disruption.
Notably, PL37 activated
mitophagy, leading to mitochondrial quality-control dysregulation and apoptosis via a mitochondria-dependent pathway, a mechanism distinct fromβ-adrenergic receptor blockade. In vivo, PL37 significantly suppressed tumor growth and angiogenesis in a hemangioma xenograft model without observable toxicity, suggesting an improved therapeutic index compared to untargeted propranolol.
Key Findings
- Mitochondria-targeted propranolol conjugate PL37 exhibited enhanced anti-hemangioma activity.
- PL37 potently inhibited endothelial cell proliferation, migration, invasion, and tube formation.
- PL37 significantly induced apoptosis in HUVECs and hemangioma-derived endothelial cells.
- PL37 triggered severe mitochondrial dysfunction and activated
mitophagy. - In vivo, PL37 significantly suppressed tumor growth and angiogenesis in a hemangioma xenograft model without toxicity.
Why It Matters
This research highlights mitochondrial targeting as a promising strategy to enhance the efficacy of existing drugs like propranolol for infantile hemangioma. By specifically inducing mitophagy and apoptosis in endothelial cells, PL37 offers a mechanism-driven approach that could potentially reduce the systemic adverse effects associated with conventional propranolol therapy. For clinicians, this opens avenues for developing next-generation anti-hemangioma agents with improved safety and efficacy profiles. While still preclinical, this work lays the groundwork for future studies to refine peptide conjugates, potentially leading to more targeted and potent treatments for vascular anomalies, moving beyond broad β-adrenergic receptor blockade.
propranolol
pl37
hemangioma
mitophagy
apoptosis
mitochondrial targeting