Non–beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

Seebauer, Caroline T.; Graus, Matthew S.; Huang, Lan; McCann, Alex; Wylie-Sears, Jill; Fontaine, Frank; Karnezis, Tara; Zurakowski, David; Staffa, Steven J.; Meunier, Frédéric A.; Mulliken, John B.; Bischoff, Joyce; François, Mathias

doi:10.1172/jci151109

Cited by 37 publications

(41 citation statements)

References 74 publications

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“…Similar to propranolol, atenolol is a chiral drug composed of S(–) and R(+) enantiomers but is selective for the β1-AR ( 11 ). A study by Lee et al showed that IH cells express very low levels of the β1-AR ( 12 ), which would exclude a role for β-AR blockade in IH and thus support the findings by Seebauer et al that R(+) enantiomers prevent IH vasculogenesis ( 9 ).…”

Section: The Use Of Propranolol For Vascular Diseasessupporting

confidence: 55%

“…The study by Seebauer et al provides a major advance in our knowledge of SOX18 as a β-AR–independent mechanistic target of propranolol and atenolol in IH ( 9 ). Since the genetic causes for IH are mostly unknown, deciphering the molecular determinants that promote the tumor growth is of fundamental importance for the advancement of this field.…”

Section: Discussionmentioning

confidence: 99%

“…In this issue of the JCI , Seebauer et al addressed this important question in the field of IH ( 9 ). Propranolol and the R(+) enantiomers of both propranolol and atenolol inhibited the differentiation of HemSCs into ECs, thereby preventing vasculogenesis in a well-established murine model of IH in which patient-derived HemSCs were injected subcutaneously into immunocompromised mice ( 10 ).…”

Section: The Use Of Propranolol For Vascular Diseasesmentioning

confidence: 99%

“…Propranolol and the R(+) enantiomers of both propranolol and atenolol inhibited the differentiation of HemSCs into ECs, thereby preventing vasculogenesis in a well-established murine model of IH in which patient-derived HemSCs were injected subcutaneously into immunocompromised mice ( 10 ). There was no difference in the efficacy of the three different treatments, and the response to both R(+) drugs was dose dependent ( 9 ). This result suggests that both propranolol and atenolol exert their efficacy through the R(+) enantiomers.…”

Section: The Use Of Propranolol For Vascular Diseasesmentioning

confidence: 99%

“…Importantly, these results raised the question of whether R(+) propranolol has a similar mode of action in the treatment of IH. In this issue of the JCI , Seebauer et al ( 9 ) demonstrated by innovative real-time, single-molecule tracking imaging that R(+) propranolol can interfere with the binding dynamics of SOX18 to chromatin in live cells. Further mechanistic studies confirmed that R(+) enantiomers of propranolol and atenolol can disrupt SOX18:RBPJ heterodimer and SOX18 homodimer formation.…”

Section: Sox18 As a Therapeutic Target In Ihmentioning

confidence: 99%

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A transcription factor is the target of propranolol treatment in infantile hemangioma

Schrenk¹,

Boscolo²

2022

Journal of Clinical Investigation

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Propranolol is a nonselective β-adrenergic receptor (AR) blocker that has been the first-line therapy for problematic infantile hemangioma (IH), the most frequent childhood vascular tumor. Although IHs are benign and eventually regress spontaneously, at least 15% of patients require treatment. Despite the extensive use of propranolol for IH treatment, its mode of action remains unclear. In this issue of the JCI , Seebauer et al. investigated the cellular and molecular consequences of propranolol treatment on IH vascular tumor formation in a murine model of IH. The efficacy of propranolol was independent of its β-AR blocker activity and was attributable to the direct targeting of the transcription factor SOX18, which, in turn, reduced hemangioma blood vessel formation. We believe these results will guide clinical translation for the use of more efficient and safer therapies for IH and possibly for other vascular anomalies in which SOX18 plays a role.

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Section: The Use Of Propranolol For Vascular Diseasessupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: The Use Of Propranolol For Vascular Diseasesmentioning

confidence: 99%

Section: The Use Of Propranolol For Vascular Diseasesmentioning

confidence: 99%

Section: Sox18 As a Therapeutic Target In Ihmentioning

confidence: 99%

See 3 more Smart Citations

A transcription factor is the target of propranolol treatment in infantile hemangioma

Schrenk¹,

Boscolo²

2022

Journal of Clinical Investigation

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SOX18 Targeting as a Potential, Viable Therapeutic Avenue for Kaposi Sarcoma

Ojala

François

2022

JAMA Dermatol

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Thiolated Chiral Naphthalene Diimide Derivatives as Effective Selectors of the β‐Blocker Atenolol Enantiomers

Kowalczyk,

Duszczyk,

Sęk

et al. 2024

Adv Funct Materials

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Atenolol β‐blocker drug (ATN) to treat hypertension and cardiovascular disorders such as angina pectoris is manufactured commercially in a racemic form, while only its (S)‐enantiomer shows selective β1‐blocking activity. Here, a new axially chiral thiolated naphthalene diimide derivatives (HS‐BIN‐NDI) for the rapid, simple, and sensitive detection of ATN enantiomers is presented. The Surface Plasmon Resonance (SPR) and Atomic Force Microscopy (AFM) experiments show that interactions between a chiral selector and a chiral analyte occur only when their configurations are opposite. The extensive computational simulations support this finding. The association coefficient determined by SPR is high (105‐106 M−1 s−1) and indicates that the interactions are electrostatic. The analytical utility of atropisomeric HS‐BIN‐NDIs is proven, and the voltammetric sensors designed to determine ATN enantiomers are constructed. The developed sensors are characterized by a wide analytical operating range from 5.0·10−3 to 1.0 µm, nanomolar detection limit, high selectivity, and a long lifetime. Several additives like urea, creatinine, glucose, human albumin, and hemoglobin do not affect ATN sensing.

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Non–beta blocker enantiomers of propranolol and atenolol inhibit vasculogenesis in infantile hemangioma

Abstract: Conflicts of interest: M.F. is involved with a startup biotech company (GBM Pty Ltd) which develops SOX18 small molecule inhibitors. F.F. and T.K. are both part of GBM 3 of 52 company and supported some of the work related to the molecular assay to measure SOX18 activity.

Cited by 37 publications

References 74 publications

A transcription factor is the target of propranolol treatment in infantile hemangioma

A transcription factor is the target of propranolol treatment in infantile hemangioma

SOX18 Targeting as a Potential, Viable Therapeutic Avenue for Kaposi Sarcoma

Thiolated Chiral Naphthalene Diimide Derivatives as Effective Selectors of the β‐Blocker Atenolol Enantiomers

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