Deoxycholic Acid (DCA), which is an FDA-approved compound for the reduction of submental fat, has evolved through an unanticipated and surprising sequence of events. Initially, it was used as a solvent for Phosphatidylcholine (PDC), which was thought to promote lipolysis, but it was later proven to be the bioactive component of the formula and is currently widely used as Kybella. It has also been used off-label to treat other types of fat deposits like lipomas, HIV lipodystrophy, and excess orbital fat. Despite widespread clinical use, there has been no consensus clarifying the mechanisms of DCA and PDC alone or in combination. Furthermore, despite PDC’s removal from the FDA-approved formula, some studies do suggest it plays an important role in fat reduction. To provide some clarity, we conducted a PubMed search and reviewed 41 articles using a comprehensive list of terms in three main categories, using the AND operator: 1) Phosphatidylcholines 2) Deoxycholic Acid, and 3) Lipoma. We isolated articles that studied PDC, DCA, and a PDC/DCA compound using cell biology, molecular and genetic techniques. We divided relevant articles into those that studied these components using histologic techniques and those that utilized specific cell death and lipolysis measurement techniques. Most morphologic studies indicated that PDC/DCA, DCA, and PDC, all induce some type of cell death with accompanying inflammation and fibrosis. Most morphologic studies also suggest that PDC/DCA and DCA alone are non-selective for adipocytes. Biochemical studies describing PDC and DCA alone indicate that DCA acts as a detergent and rapidly induces necrosis while PDC induces TNF-α release, apoptosis, and subsequent enzymatic lipolysis after at least 24 hours. Additional papers have suggested a synergistic effect between the two compounds. Our review integrates the findings of this growing body of literature into a proposed mechanism of fat reduction and provides direction for further studies.
Here we explore the role of Interleukin-17 (IL-17) in the promotion of radiation dermatitis (RD) and radiation therapy (RT) efficacy. RD is a common and potentially treatment-limiting skin toxicity that occurs following RT. When the treated tumor is close to the skin, as in head and neck or breast cancer, RD is the most common acute adverse event which negatively impacts patients’ quality of life; however, evidence-based treatments are limited. We performed RNA sequencing of RT-treated skin in both human skin and a murine model, which each showed increased expression of IL-17 Receptor type C (IL-17RC). To further explore the role of the IL-17 pathway in the development of RD, both genetic knockout of IL-17RC and pharmacologic blocking of IL-17A in mouse models were studied, and both were found to have attenuated histopathological signs of RD, including inflammation, acanthosis, and fibrosis when compared to controls. After establishing the importance of the IL-17 pathway on RD, we explored the impact of such IL-17 pathway modification on the anti-tumorigenic efficacy of RT, an important step when considering a future IL-17 neutralizing therapy for RD. A Trans-PyMT murine model of triple-negative breast cancer was used to evaluate the impact of IL-17A neutralization on RT efficacy. There was no difference found in the efficacy of RT in mice treated with IL-17A neutralizing antibody as compared with saline control. Overall, we present a clinically relevant murine model which advances our understanding of the immunopathogenesis of RD and suggests further exploration of targeted therapies for RD prophylaxis is warranted. Additionally, we show that modifying the IL-17 pathway is effective in mitigating RD phenotype with no impact on RT efficacy.
Citation Format: Megan E. Pirtle, Yana Kost, Alana Deutsch, Kosaku Shinoda, Beth N. McLellan. Exploring the impact of IL-17 pathway modification on radiation dermatitis and radiation therapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2833.
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