Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia

Pierre-Luc Mouchel (1, 2) , Nizar Serhan (2) , Rémy Bétous (3, 4) , Thomas Farge (2) , Estelle Saland (2) , Philippe de Médina (5) , Jean-Sébastien Hoffmann (6, 1) , Jean-Emmanuel Sarry (2) , Marc Poirot (3, 2) , Sandrine Silvente-Poirot (2) , Christian Récher (2, 1)

1 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
2 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
3 CRCT - Centre de Recherches en Cancérologie de Toulouse
4 Équipe labellisée Ligue Nationale Contre le Cancer [Toulouse]
5 Affichem SAS [Toulouse]
6 Laboratoire d’Excellence ‘TOUCAN’ [Toulouse]

Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients.

Mots clés: AML; CLDX; DDA; DNA damage; LXR; anthracycline; autophagy; dendrogenin A; primary sample; synergy.

Domaines: Sciences du Vivant [q-bio]

Pierre-Luc Mouchel, Nizar Serhan, Rémy Bétous, Thomas Farge, Estelle Saland, et al.. Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia. Cancers, 2020, 12 (10), pp.2933. ⟨10.3390/cancers12102933⟩. ⟨inserm-03084630⟩