New insights on propranolol for hemangiomas
Clinical Applications
Dr. Schwarzenberger is the former physician editor of DermWorld. She interviews the author of a recent study each month.
By Kathryn Schwarzenberger, MD, March 1, 2020
In this month’s Clinical Applications column, Physician Editor Kathryn Schwarzenberger, MD, talks with Jack L. Arbiser, MD, PhD, about his recent Nature Precision Oncology article "Propranolol exhibits activity against hemangiomas independent of beta blockade."
Dr. Schwarzenberger: You and your colleagues recently published what I anticipate will be regarded as a very important article about propranolol and infantile hemangiomas. Since I suspect that many dermatologists do not regularly read Nature Precision Oncology, could you briefly explain what you were studying here?
Dr. Arbiser: I had long been interested in the mechanism of propranolol in hemangiomas. I questioned the assumption that propranolol works through beta blockade on hemangiomas because clinically, when patients treated with propranolol undergo resolution of hemangiomas, the lesions look white, rather than red. Propranolol is a vasodilator because of beta blockade, and the hemangiomas look vasoconstricted. That was the first clue for me that propranolol was doing something else.
We treated hemangioma stem cells with both isoforms of propranolol and found that the gene most downregulated was Angiopoietin like 4 (Angptl4). When we sought to confirm this using Western blots using a hemangioma murine cell line, we found that only R-propranolol, which is the non-beta blocking isomer of propranolol, caused downregulation of Angptl4, while S-propranolol (beta blocker) had no effect. We demonstrated that R-propranolol can inhibit the growth of bend 3 endothelial tumors in mice, and moreover, R-propranolol induced beneficial genes in the vascular lesion including high-density lipoprotein (HDL) and betaine homocysteine methyl transferase (BHMT) which gets rid of homocysteine. Thus, our findings might be of interest to cardiologists too.
Dr. Schwarzenberger: What do we know to date about the pathogenesis of infantile hemangiomas? Did your study provide any new information?
Dr. Arbiser: We still know little about the pathogenesis. Many experienced groups have looked for point mutations and have not found them. I believe that if hemangiomas were caused by mutations, we would have found them already. Given the lack of known mutations, I think that hemangiomas arise from epigenetic changes perhaps caused by hypoxia in the fetus or placenta, and endothelial cells are imprinted by their environmental exposure to form hemangiomas. Estrogen plays a role as well, as there is a female predominance to hemangiomas. In terms of pathogenesis, we found that propranolol induces respiration, and hemangiomas use a predominantly glycolytic metabolism.
Dr. Schwarzenberger: The rather serendipitous finding that propranolol shrinks infantile hemangiomas certainly rocked the pediatric dermatology world and, for the first time, provided us an effective way to treat these challenging lesions. Did your study help us better understand how this drug works its magic?
Dr. Arbiser: Yes. We had previously shown in a study of patients with hemangiomas that propranolol decreases vascular endothelial growth factor (VEGF), but not Angiopoietin 2. In this study, we found that R-propranolol decreases Angptl4. In the presence of angiogenic factors like VEGF and Angplt4, Angiopoietin-2 maintains hemangiomas, but if you take away the angiogenic factors, Angiopoietin-2 causes regression. We feel that this mechanism may also account for the epidemiologic findings that associate propranolol use with decreased incidence of cancers like melanoma.
It is indeed serendipitous that commercial propranolol exists as a mixture of R and S isomers rather than the pure S-isomer beta blocker. The R-propranolol is regarded as an “inactive” metabolite not worth purifying out, and it might be that if infants were given pure S-propranolol for hypertension, it would have no effect on hemangiomas. It is thus the likely “inactive” impurity in propranolol that accounts for its benefits against hemangiomas (and possibly other tumors).
Dr. Schwarzenberger: Are you aware of any other drugs that we use that exist as stereoisomers with differential effects?
Dr. Arbiser: A notorious example is thalidomide, where the R isomer is a sedative and the S isomer is teratogenic. Another example is dexmethylphenidate (focalin) used for the treatment of ADHD. Dr. Schwarzenberger: It's exciting to imagine being able to use a form of propranolol without beta-blocker effects. Are there any potential unintended consequences of using only the “active” isomer?
Dr. Arbiser: This remains to be seen. We have not observed any toxic effects of R-propranolol in mice.
Dr. Schwarzenberger: What's next? When can we hope to have this available for use on our patients?
Dr. Arbiser: This is all a question of funding. We are looking to license R-propranolol and depending on the speed of development, it should be a matter of a few years.
Jack L. Arbiser, MD, PhD is a Thomas J. Lawley professor of dermatology in the department of dermatology at Emory University School of Medicine. He is a member of the Winship Cancer Institute and serves as a staff physician at the division of dermatology in the Atlanta VA Medical Center. Emory University is applying for a patent on R-propranolol based upon the Arbiser lab discovery. His article appeared in Nature Precision Oncology.
Disclaimer: The views and opinions expressed in this article do not necessarily reflect those of DW.
