Florean C., Kim K. R., Schnekenburger M., Kim H. J., Moriou C., Debitus Cécile, Dicato M., Al-Mourabit A., Han B. W., Diederich M. (2018). Synergistic AML cell death induction by marine cytotoxin (+)-1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-fistularin-3 and bcl-2 inhibitor Venetoclax. Marine Drugs, 16 (12), p. art. 518 [19 p.]. ISSN 1660-3397.
Titre du document
Synergistic AML cell death induction by marine cytotoxin (+)-1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-fistularin-3 and bcl-2 inhibitor Venetoclax
Année de publication
2018
Auteurs
Florean C., Kim K. R., Schnekenburger M., Kim H. J., Moriou C., Debitus Cécile, Dicato M., Al-Mourabit A., Han B. W., Diederich M.
Source
Marine Drugs, 2018,
16 (12), p. art. 518 [19 p.] ISSN 1660-3397
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(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge Suberea clavata, 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 Subarea clavata is in fact the (+)-11(R), 17(S)-fistularin-3 stereoisomer keeping the known configuration 1(R), 6(S), 1'(R), and 6'(S) 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.
Plan de classement
Sciences fondamentales / Techniques d'analyse et de recherche [020]
;
Substances naturelles [035]
;
Santé : généralités [050]
Localisation
Fonds IRD [F B010074875]
Identifiant IRD
fdi:010074875
