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Mouchel PL, Serhan N, Betous R, et al. Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia. Cancers (Basel). 2020;12(10)doi: 10.3390/cancers12102933.
Mouchel, P. L., Serhan, N., Betous, R., Farge, T., Saland, E., De Medina, P., Hoffmann, J. S., Sarry, J. E., Poirot, M., Silvente-Poirot, S., & Récher, C. (2020). Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia. Cancers, 12(10), . https://doi.org/10.3390/cancers12102933
Mouchel, Pierre-Luc, et al. "Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia." Cancers vol. 12,10 (2020). doi: https://doi.org/10.3390/cancers12102933
Mouchel PL, Serhan N, Betous R, Farge T, Saland E, De Medina P, Hoffmann JS, Sarry JE, Poirot M, Silvente-Poirot S, Récher C. Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia. Cancers (Basel). 2020 Oct 12;12(10). doi: 10.3390/cancers12102933. PMID: 33053669; PMCID: PMC7601603.
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Cancers (Basel). 2020 Oct 12;12(10). doi: 10.3390/cancers12102933.

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

Cancers

Pierre-Luc Mouchel, Nizar Serhan, Rémy Betous, Thomas Farge, Estelle Saland, Philippe De Medina, Jean-Sébastien Hoffmann, Jean-Emmanuel Sarry, Marc Poirot, Sandrine Silvente-Poirot, Christian Récher

Affiliations

  1. Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, 31059 Toulouse, France.
  2. Centre de Recherches en Cancérologie de Toulouse, UMR1037, Inserm, Université de Toulouse 3 Paul Sabatier, Equipe Labellisée LIGUE 2018, F-31037 Toulouse, France.
  3. Team "Cholesterol Metabolism and Therapeutic Innovations", Cancer Research Center of Toulouse (CRCT), UMR 1037, Inserm-Université de Toulouse 3, Equipe labellisée par la ligue contre le cancer, 31037 Toulouse, France.
  4. CRCT, Université de Toulouse, Inserm, CNRS, UPS, 31000 Toulouse, France.
  5. Equipe Labellisée Ligue Contre le Cancer, Laboratoire d'Excellence Toulouse Cancer, 31037 Toulouse, France.
  6. Affichem SAS, 31400 Toulouse, France.
  7. Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Laboratoire de pathologie, Institut Universitaire du Cancer-Toulouse, Oncopole, 31037 Toulouse, France.

PMID: 33053669 PMCID: PMC7601603 DOI: 10.3390/cancers12102933

Abstract

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.

Keywords: AML; CLDX; DDA; DNA damage; LXR; anthracycline; autophagy; dendrogenin A; primary sample; synergy

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