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Open AccessArticle

Dendrogenin A Synergizes with Cytarabine to Kill Acute Myeloid Leukemia Cells In Vitro and In Vivo

1
Unité Mixte de Recherche (UMR) 1037, Cancer Research Center of Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) Université de Toulouse, Team Cholesterol Metabolism and Therapeutic Innovations, Equipe labellisée par la Ligue Contre le Cancer, 31037 Toulouse, France
2
Cancer Research Center of Toulouse (CRCT), Unité Mixte de Recherche (UMR) 1037 Inserm/Université Toulouse III-Paul Sabatier, ERL5294 Centre national de la recherche scientifique (CNRS), Team Drug Resistance and Oncometabolism in Acute Myeloid Leukemia, 31037 Toulouse, France
3
Service d’Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Université de Toulouse, 31400 Toulouse, France
4
AFFICHEM, 31400 Toulouse, France
5
Dendrogenix, 4000 Liège, Belgium
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Laboratory of Mass Spectrometry, Institut National de la Santé et de la Recherche Médicale (INSERM) ERL 1157, Centre national de la recherche scientifique (CNRS) Unité Mixte de Recherche (UMR) 7203 LBM, Sorbonne Universités-UPMC, CHU Saint-Antoine, 75012 Paris, France
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(7), 1725; https://doi.org/10.3390/cancers12071725
Received: 21 May 2020 / Revised: 19 June 2020 / Accepted: 25 June 2020 / Published: 29 June 2020
(This article belongs to the Special Issue Targeted Cancer Therapy)
Dendrogenin A (DDA) is a mammalian cholesterol metabolite that displays potent antitumor properties on acute myeloid leukemia (AML). DDA triggers lethal autophagy in cancer cells through a biased activation of the oxysterol receptor LXRβ, and the inhibition of a sterol isomerase. We hypothesize that DDA could potentiate the activity of an anticancer drug acting through a different molecular mechanism, and conducted in vitro and in vivo combination tests on AML cell lines and patient primary tumors. We report here results from tests combining DDA with antimetabolite cytarabine (Ara-C), one of the main drugs used for AML treatment worldwide. We demonstrated that DDA potentiated and sensitized AML cells, including primary patient samples, to Ara-C in vitro and in vivo. Mechanistic studies revealed that this sensitization was LXRβ-dependent and was due to the activation of lethal autophagy. This study demonstrates a positive in vitro and in vivo interaction between DDA and Ara-C, and supports the clinical evaluation of DDA in combination with Ara-C for the treatment of AML. View Full-Text
Keywords: Acute myeloid leukemia; Dendrogenin A; tumor suppressor; cholesterol metabolism; synergy; primary cancer cells Acute myeloid leukemia; Dendrogenin A; tumor suppressor; cholesterol metabolism; synergy; primary cancer cells
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Serhan, N.; Mouchel, P.-L.; de Medina, P.; Segala, G.; Mougel, A.; Saland, E.; Rives, A.; Lamaziere, A.; Despres, G.; Sarry, J.-E.; Larrue, C.; Vergez, F.; Largeaud, L.; Record, M.; Récher, C.; Silvente-Poirot, S.; Poirot, M. Dendrogenin A Synergizes with Cytarabine to Kill Acute Myeloid Leukemia Cells In Vitro and In Vivo. Cancers 2020, 12, 1725.

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