Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, United States.
Elife. 2019 Jul 30;8:e43026. doi: 10.7554/eLife.43026.
Propranolol is an approved non-selective β-adrenergic blocker that is first line therapy for infantile hemangioma. Despite the clinical benefit of propranolol therapy in hemangioma, the mechanistic understanding of what drives this outcome is limited. Here, we report successful treatment of pericardial edema with propranolol in a patient with Hypotrichosis-Lymphedema-Telangiectasia and Renal (HLTRS) syndrome, caused by a mutation in . Using a mouse pre-clinical model of HLTRS, we show that propranolol treatment rescues its corneal neo-vascularisation phenotype. Dissection of the molecular mechanism identified the R(+)-propranolol enantiomer as a small molecule inhibitor of the SOX18 transcription factor, independent of any anti-adrenergic effect. Lastly, in a patient-derived in vitro model of infantile hemangioma and pre-clinical model of HLTRS we demonstrate the therapeutic potential of the R(+) enantiomer. Our work emphasizes the importance of SOX18 etiological role in vascular neoplasms, and suggests R(+)-propranolol repurposing to numerous indications ranging from vascular diseases to metastatic cancer.
普萘洛尔是一种已被批准的非选择性β肾上腺素能阻滞剂，是治疗婴儿血管瘤的一线药物。尽管普萘洛尔治疗血管瘤具有临床益处，但对其作用机制的理解有限。在这里，我们报告了一例由 基因突变引起的 Hypotrichosis-Lymphedema-Telangiectasia and Renal (HLTRS) 综合征患者使用普萘洛尔成功治疗心包水肿的病例。使用 HLTRS 综合征的小鼠临床前模型，我们表明普萘洛尔治疗可挽救其角膜新生血管化表型。分子机制的剖析确定了 R(+)-普萘洛尔对映体是 SOX18 转录因子的小分子抑制剂，与任何抗肾上腺素能作用无关。最后，在婴儿血管瘤的患者来源体外模型和 HLTRS 的临床前模型中，我们证明了 R(+)对映体的治疗潜力。我们的工作强调了 SOX18 在血管肿瘤中的病因作用的重要性，并提示 R(+)-普萘洛尔可重新用于从血管疾病到转移性癌症等多种适应症。
