Abstract 684: Inhibition of translation by aglaiastatins: Mechanism of action
Authors: Rayelle Itoua Maïga, Regina Cencic, Jennifer Chu, Lauren E. Brown, Daniel Dirck Waller, Mònica Gómez Palou, Michael Sebag, John A. Porco, Jerry Pelletier
Journal: Cancer Research (2018)

Abstract Background: Secondary metabolites from plants of the Aglaia genus consist of several classes of compounds, including the cyclopenta[b]benzopyrans, benzo[b]oxepines and cyclopenta[b]benzofurans (rocaglates). The best characterized of these is silvestrol; a rocaglate, which has been shown to target eukaryotic initiation factor 4A (eIF4A), the RNA helicase subunit of the eukaryotic initiation factor 4F (eIF4F) complex. The formation of this complex is regulated by the PI3K/mTOR and Ras-MAPK pathways. Hence, being at the nexus of important oncogenic pathways, eIF4F represents an attractive target for cancer therapy. Silvestrol and its analogs have demonstrated potent activity in human tumor cell lines and xenograft models. Some of the most responsive mRNAs are those encoding oncogenic proteins such as Myc and Mcl-1. This places this group of compounds as promising therapeutic agents against Myc-driven cancers. Purpose of the study: The purpose of this study is to characterize a sub-group of Aglaia secondary metabolites known as aglaiastatins, which are characterized by the presence of a pyrimidone subunit fused to the cyclopenta[b]benzofuran structure, resulting in a pentacyclic skeleton. Method: Using in vitro and in vivo assays, we assessed the potency of representative aglaiastatins towards inhibition of protein synthesis and cytotoxicity of tumor cells. Results: We showed that aglaiastatins induce a specific inhibition of cap-dependent translation by interfering with eIF4A's RNA binding activity, similar to rocaglates. This strong correlation in the mechanism of action was further demonstrated in an eIF4AF163L rocaglate-resistant cell line. Aglaiastatins also demonstrated single agent potency in vitro against a diverse panel of human lymphoma cell lines as well as primary patient samples. In vivo, the compound of interest was found to have a chemosensitization capability, by reversing chemoresistance to doxorubicin in a pre-clinical murine lymphoma model. Conclusion: Our results indicate that the aglaiastatins also target eIF4A, similarly to rocaglates. Their activity against rocaglate-resistant cells indicates a high similarity in drug target binding pattern. Moreover, the targeting of cap-dependent translation through the RNA helicase allows for the potent activity of the drug against several lymphoma lines, regardless of their mutational landscape, thus providing a potential therapeutic opportunity against difficult-to-treat hematological malignancies. Citation Format: Rayelle Itoua Maïga, Regina Cencic, Jennifer Chu, Lauren E. Brown, Daniel Dirck Waller, Mònica Gómez Palou, Michael Sebag, John A. Porco, Jerry Pelletier. Inhibition of translation by aglaiastatins: Mechanism of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 684.