Abstract B045: Structure-activity relationship study of a novel PKC activator, vibsanin A, for induction of differentiation in leukemia cells

Abstract

Abstract Background and Objective: Chemotherapeutic agents are widely used for acute myeloid leukemia (AML) treatment; however, their severe side effects in patients limit the clinical use of chemotherapy for AML. Differentiation-inducer such as PKC activators was expected to show therapeutic potentials, but many natural derived PKC activators, including phorbol 12-myrystate 13-acetate (PMA), act as tumor-promoting activity. Therefore, the development of differentiation inducing-agents may contribute to constructing the next-generation AML treatment. Vibsanin A (VibA) was recently reported to induce differentiation of myeloid leukemia cells by activating PKC and to prolong survival of mouse xenograft model; however, the detailed chemical feature of VibA remains unclear. In this study, to determine the key partial structure of VibA for its activity, we compared the activity of VibA analogs in the activation of PKC and differentiation of AML cells. Results: To know whether the analogs functioned as PKC activator similarly to VibA, we detected phosphorylation of ERK, which acts downstream of PKC, by Western blotting. As a result, only one analog (VibA-1) induced ERK phosphorylation in a dose-dependent manner like PMA and VibA; however, other analogs had no effect on ERK phosphorylation. We examined whether VibA-1-induced ERK phosphorylation was mediated by PKC activation as well as VibA. We treated with PMA of the cells for long term to downregulate PKC. VibA-1-induced ERK phosphorylation was suppressed by pretreatment with PMA for the long term, indicating that VibA-1 activated PKC, thereby ERK phosphorylation. These data suggested that only VibA-1 retained the ability to activate PKC, which was originally observed in VibA. We observed that VibA-1-treated THP-1 cells became adherent to the culture plate and showed considerable morphologic change. Moreover, several lines of evidences including increased cell size, lowered nuclear to cytoplasmic ratio, and highly vacuolated cytoplasm, characterized by Giemsa staining suggested, that VibA-1 triggered monocytic differentiation similarly to VibA. Thus, our results suggested that VibA and/or its analog VibA-1 may be a novel chemotherapeutic agent for treatment of AML. Citation Format: Siro Simizu, Wataru Matsuki. Structure-activity relationship study of a novel PKC activator, vibsanin A, for induction of differentiation in leukemia cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B045.