Blockade of beta-adrenergic receptors reduces cancer growth and enhances the response to anti-CTLA4 therapy by modulating the tumor microenvironment

The development of immune checkpoint inhibitors (ICI) marks an important breakthrough of cancer therapies in the past years. However, only a limited fraction of patients benefit from such treatments, prompting the search for immune modulating agents that can improve the therapeutic efficacy. The nonselective beta blocker, propranolol, which for decades has been prescribed for the treatment of cardiovascular conditions, has recently been used successfully to treat metastatic angiosarcoma. These results have led to an orphan drug designation by the European Medicines Agency for the treatment of soft tissue sarcomas. The anti-tumor effects of propranolol are suggested to involve the reduction of cancer cell proliferation as well as angiogenesis. Here, we show that oral administration of propranolol delays tumor progression of MCA205 fibrosarcoma model and MC38 colon cancer model and increases the survival rate of tumor bearing mice. Propranolol works by reducing tumor angiogenesis and facilitating an anti-tumoral microenvironment with increased T cell infiltration and reduced infiltration of myeloid-derived suppressor cells (MDSCs). Using T cell deficient mice, we demonstrate that the full anti-tumor effect of propranolol requires the presence of T cells. Flow cytometry-based analysis and RNA sequencing of FACS-sorted cells show that propranolol treatment leads to an upregulation of PD-L1 on tumor associated macrophages (TAMs) and changes in their chemokine expression profile. Lastly, we observe that the co-administration of propranolol significantly enhances the efficacy of anti-CTLA4 therapy. Our results identify propranolol as an immune modulating agent, which can improve immune checkpoint inhibitor therapies in soft tissue sarcoma patients and potentially in other cancers.

Infantil Hemangioma and Optimum Dose of Propranolol Treatment: A Retrospective Tertiary-Center Study

Background/Objectives: Propranolol is the mainstay treatment of infantile hemangioma, and the optimal dose is unclear. Few studies are comparing the efficacy of propranolol dose of 2 vs.3 mg/kg/day. We compared the efficacy between these two doses and propranolol groups with no treatment group. Methods: One hundred eight patients with infantile hemangioma (15 days-27 months of age) were examined. The patients with high-risk features and/or a score of >6 points are given propranolol with a final dose of 2 or 3 mg/kg/day according to tolerance for 6-12 months. The resolutions rates for propranolol vs. placebo and propranolol 2 mg/kg/day vs. 3 mg/kg/day are compared. Results: The demographic and clinical features of the groups ( the non-treatment, propranolol 2 mg/kg/day group, propranolol 3 mg/kg/day group) are similar. Propranolol is significantly efficent in infantil hemangioma treatment (p<0.001). The resolution rates are not statistically different between 2 mg/kg/day propranolol group vs 3 mg/kg/day propranolol group at the sixth (68,59 ± 28,95 vs 73,44 ± 32,54)(p=0,673) and twelfth month (p=0,673) (89,08 ± 46,58 vs 91,13 ± 37,46 respectively )of follow up. A milld (n=3)(4%) adverse event was reported with no need for cessation.Conclusions: Propranolol is a safe drug for treating infantile hemangioma with an ideal dose of 2 mg/kg/day rather than 3 mg/kg/day.

Propranolol significantly reduced DNA polymerase β expression in patients with essential tremor

Background Essential tremor (ET) is the most common movement disorder. Propranolol is a first-line medication for ET. We aimed to evaluate the effect of propranolol on the expression of poly (ADP-ribose) polymerase 1 (PARP1) and DNA polymerase beta (POLB) genes, which are known to be related to neurodegenerative diseases, in patients with ET. MethodsThirty-five healthy volunteers and thirty-five patients followed up with essential tremors were included in a non-randomized control experimental study. Expressions of PARP1 and POLB genes were compared between the control group and the patient group. In addition, pre- and post-treatment gene expression levels and Fahn-Tolosa-Marin tremor scale values of the patient group were compared after 8 weeks of propranolol treatment. The Wilcoxon rank and Mann Whitney U tests were used to analyze the data. ResultsAt baseline, PARP1 expression was significantly lower in the ET group than in the control group. (p<0.001). POLB gene expression was significantly higher in the pre-treatment ET group than in the controls (p<0.05). There was no significant difference in PARP1 expression levels before and after 8 weeks of propranolol treatment. POLB gene expression was significantly higher in the pre-treatment group than in the post-treatment group (p<0.001). ConclusionPropranolol significantly decreased POLB gene expression but there was no significant difference in PARP1 gene expression levels in the patient group, after 8 weeks of propranolol treatment.

Propranolol treatment of infantile subglottic hemangioma: a report of two cases and a literature review

Infantile hemangioma is one of the most common benign tumors of infancy. The natural evolution includes rapid growth followed by gradual involution. Airway hemangiomas are not that common, but they can lead to dyspnoea, as well as to life-threatening complications. Two children aged 3 months were admitted to the Pediatric Department with difficulties in breathing and with biphasic stridor. They had previously been hospitalized because of the same symptoms and misdiagnosed as having an upper respiratory tract infection. The previous treatment included intravenous or inhaled corticosteroids, without any significant improvement. Laryngoscopy was&nbsp;performed for both of the children. There was a mass in the subglottic area with the appearance of a hemangioma causing significant airway stenosis. We started treatment with propranolol at a dose of 1 mg/kg/day twice daily. The dose was gradually increased up to 3 mg/kg/day, under close monitoring. In the first 7 to 10 days after initiation of treatment, we observed a significant improvement of the respiratory distress. The second laryngoscopy showed an almost complete involution of the mass in the subglottis.&nbsp; The focus of this article will be primarily on the clinical presentation and the therapeutic response of subglottic hemangioma, along with a literature review on the subject.

Recurrent Graves’ disease post SARS-CoV-2 infection

A 22-year-old woman was diagnosed with thyrotoxicosis 8 weeks after the diagnosis of a mild COVID-19 infection. She had reported significant unexplained weight loss after testing positive for COVID-19, but failed to seek medical attention. She recovered well from COVID-19, but presented to the emergency department with worsening symptoms of thyrotoxicosis after 2 months. In view of her known history of previously treated Graves’ disease, a recurrence of Graves’ thyrotoxicosis was suspected. A positive thyroid stimulating hormone receptor antibody confirmed the diagnosis. She was started on carbimazole and propranolol treatment with significant improvement of her symptoms.

STRATEGY AND EXPERIENCE OF INFANTILE HEMANGIOMA TREATMENT

Objective. To analyze the treatment results of patients with infantile hemangiomas using various methods. Methods. The study is grounded on the treatment results of children (n=189) with infantile hemangiomas during the period of 2000-2018 years. All patients were divided into the groups: 1) dynamic observation - 23 (12.2%) children; 2) local destruction - 78 (41.3%); 3) surgical treatment - 22 (11.6%); 4) drug therapy - 66 (34.9%) patients. The interstitial coagulation (n=28) and electrocoagulation of hemangioma (n=50) were applied for the local destruction. 18 patients underwent the complete removal of hemangioma and 4 - segmental resection of tumor with the subsequent propranolol treatment. Propranolol was used for the drug treatment and it was combined with the topical application of timolol (n=13). Results. Hemangioma regression was registered in 18 (78.3%) patients of the first group. Among the patients of the second group, involution of hemangioma was observed in 26 (92.6%) patients when the interstitial coagulation was applied and 2 (7.4%) children had hemangioma recurrence. A strongpositiveeffect can be reached by electrocoagulation of superficial hemangiomas (all patients). With primary radical intervention, complete cure was noted in all children, and with segmental resection only one (4.5%) child had a relapse. Keloid scars were formed in 3 (13.6%) children after surgery. Propranolol seemed to be effective in treating hemangiomasinchildrenof all ages, and in 41 (62.1%) patients hemangiomas completely disappeared. Conclusion. Before initiatingtherapy, thechildrenneed to be assessed for the contraindications and the treatment strategy.In case of infantile hemangioma should be individual based on the results of clinical investigation. Systemic propranolol treatment has gained rapid popularity as the treatment of choice for infantile hemangiomas and may be applied not only as the basic treatment, but also in combination with other methods. Surgical removal of hemangioma remains one of the common treatments components for children with infantile hemangiomas. What this paper adds Different variants of infantile hemangioma treatment have been analyzed: ranging from dynamic observation to surgical and systemic treatment. It has been shown, that in case of infantile hemangiomas, Beta-blockers have become the treatment of choice in case of the absence of contraindications; and surgical treatment is indicated in children with the risk of complications development.

O uso do propranolol na terapêutica do hemangioma infantil

Objetivo: Avaliar o uso do propranolol como opção terapêutica para o hemangioma infantil, descrevendo as evidências encontradas na literatura, acerca das vantagens desta nova terapêutica quando comparada às terapias convencionais. Métodos: Trata-se de uma revisão integrativa de literatura, com artigos nas bases de dados Biblioteca Virtual de Saúde (BVS) e PubMed, nos idiomas português e inglês, utilizando os descritores “propranolol treatment”, “propranolol”, “infantile hemangioma” e “hemangioma of infancy”. Resultados: Foram encontrados na busca de literatura 1876 artigos, nos quais após a aplicação dos critérios de inclusão e exclusão e a revisão em pares ficaram 18 artigos a serem lidos na íntegra. Dos 18 artigos, foram incluídos 1380 pacientes que preencheram os critérios de inclusão. Um total de 56.5% eram do sexo feminino e compreendiam o intervalo de idade de 1 semana de vida a 9 anos de idade. Considerações Finais: O propranolol é considerado uma terapia alternativa para o tratamento do hemangioma infantil por apresentar uma eficácia elevada e menos efeitos adversos.

Blockade of β-Adrenergic Receptors by Propranolol Disrupts Reconsolidation of Drug Memory and Attenuates Heroin Seeking

Persistent traces of drug reward memories contribute to intense craving and often trigger relapse. A number of pharmacological interventions on drug-associated memories have shown significant benefits in relapse prevention at a preclinical level but their translational potential is limited due to deleterious side effects. Propranolol, a non-specific β-adrenergic receptors antagonist, is known for its ability to erase maladaptive memories associated with nicotine or cocaine in rodents and humans. However, little is known about its effect on reconsolidation of heroin memory and heroin seeking. In the present study, rats with a history of intravenous heroin self-administration received the propranolol treatment (10 mg/kg; i.p.) at different time windows with or without CS (conditioned stimulus) exposure. Our results showed that propranolol, when administered immediately after CS exposure but not 6 h later, can significantly attenuate cue-induced and drug-primed reinstatement of heroin seeking, suggesting that propranolol has the ability to disrupt heroin memory and reduce relapse. The propranolol treatment without retrieval of drug memory had no effect on subsequent reinstatement of heroin seeking, suggesting that its interfering effects are retrieval-dependent. Importantly, the effects of propranolol were long lasting as rats showed diminished drug seeking even 28 days after the treatment. Altogether, our study suggests that propranolol can interfere with reconsolidation of heroin memory and reduce subsequent drug seeking, making it an attractive therapeutic candidate for the treatment of opioid addiction and relapse prevention.