Abstract 1642: Bryostatin 1 and the simplified analog Merle 23 have similar and opposing properties on mouse epidermal cells and mouse skin

Abstract

Abstract Protein kinase C (PKC) is differentially regulated in a range of cancers and has become an attractive therapeutic target. A number of natural compounds exist that have been found to regulate PKCs, and the biological responses of each compound can vary. The PKC activator PMA is an established tumor promoter, while others, such as the bryostatins, are non-tumor promoting and have inhibitory effects on the PKC pathway. Because of its effects on the PKC pathway, bryostatin 1 is currently in clinical trials as an anti-cancer agent. Limited availability and the difficulty involved in synthesizing bryostatin 1 make its use as an anti-cancer agent less attractive. Merle 23, a simplified synthetic analog of bryostatin 1, could be an alternative to bryostatin 1 if it acted similarly. Initial investigations of Merle 23 have revealed biological responses both similar to bryostatin 1 and similar to PMA, depending on the system. In U937 leukemia cells Merle 23 acts similar to PMA, and in the LNCaP prostate cancer cell line it behaves more like bryostatin 1. Its behavior in mouse skin is of particular interest, since this is the system in which the tumor promoting activity of PMA and the anti-tumor promoting activity of bryostatin 1 have been characterized. The activity of Merle 23 was compared to PMA and bryostatin 1 in mouse epidermal cells and mouse skin. In mouse primary keratinocytes PMA produces a prolonged morphological response, while the morphological response to bryostatin 1 is transient. The response to Merle 23 is intermediate, but more similar to bryostatin 1. When applied simultaneously, Merle 23, like bryostatin 1, is able to protect the cells from the morphological response induced by PMA. In the PKC pathway, all three compounds promote similar levels of initial PKCδ activation and ERK1/2 phosphorylation. By 24 hrs, however, the responses differ. At high concentrations, bryostatin 1 protects PKCδ from down regulation whereas Merle 23 does not. Bryostatin 1 is also much more potent for down regulation of PKCα, whereas Merle 23 and PMA are similar. The inflammatory response was measured by monitoring the transcript levels of various genes involved in inflammation. PMA induced the largest increase in transcript levels, while Merle 23 was more similar to bryostatin 1. Short-term in vivo analysis reveals no epidermal thickening in response to low doses of Merle 23 whereas the corresponding dose of PMA induced significant hyperplasia. The in vivo analysis of Merle 23 is ongoing. The results presented suggest that Merle 23 behaves more similarly to bryostatin 1 in the mouse epidermal cells at the level of biological response, raising the possibility that it may likewise be non-promoting. The results emphasize that the structure activity relations responsible for the distinct behavior between PMA and bryostatin 1 are distinct for different cellular systems and different biological endpoints. Citation Format: Jessica Kelsey, Noemi Kedei, Christophe Cataisson, Mark Petersen, Stuart Yuspa, Gary Keck, Peter Blumberg. Bryostatin 1 and the simplified analog Merle 23 have similar and opposing properties on mouse epidermal cells and mouse skin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1642. doi:10.1158/1538-7445.AM2014-1642