Synergistic AML Cell Death Induction by Marine Cytotoxin (+)-1(<i>R</i>), 6(<i>S</i>), 1’(<i>R</i>), 6’(<i>S</i>), 11(<i>R</i>), 17(<i>S</i>)-Fistularin-3 and Bcl-2 Inhibitor Venetoclax

• Main Authors: Cristina Florean, Kyung Rok Kim, Michael Schnekenburger, Hyun-Jung Kim, Céline Moriou, Cécile Debitus, Mario Dicato, Ali Al-Mourabit, Byung Woo Han, Marc Diederich
• Format: Article
• Language: English
• Published: MDPI AG 2018-12-01
• Series: Marine Drugs
• Subjects: acute myeloid leukemia; ABT-199; Mcl-1; bromotyrosine; (+)-11(<i>R</i>), 17(<i>S</i>)-fistularin-3; configuration; anticancer drug combination
• Online Access: https://www.mdpi.com/1660-3397/16/12/518

Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy to eradicate resistant AML cells. We show here that 1(<i>R</i>), 6(<i>S</i>), 1&#8217;(<i>R</i>), 6&#8217;(<i>S</i>), 11(<i>R</i>), 17(<i>S</i>)-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge <i>Suberea clavata</i>, synergizes with Bcl-2 inhibitor ABT-199 to efficiently kill Mcl-1/Bcl-2-positive AML cell lines, associated with Mcl-1 downregulation and endoplasmic reticulum stress induction. The absolute configuration of carbons 11 and 17 of the fistularin-3 stereoisomer was fully resolved in this study for the first time, showing that the fistularin we isolated from the marine sponge <i>Subarea clavata</i> is in fact the (+)-11(<i>R</i>), 17(<i>S</i>)-fistularin-3 stereoisomer keeping the known configuration 1(<i>R</i>), 6(<i>S</i>), 1&#8217;(<i>R</i>), and 6&#8217;(<i>S</i>) for the verongidoic acid part. Docking studies and in vitro assays confirm the potential of this family of molecules to inhibit DNA methyltransferase 1 activity.