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

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.

Targeting cholesterol homeostasis in hematopoietic malignancies

“… 44 The combination of DDA and idarubicin synergistically enhanced the autophagic cell death in AML cells, maximizing DNA damage induced by idarubicin and decreasing DNA repair. 45 Differently from the results reported in CD34 + AML cells treated with lovastatin, 39 the induction of lethal autophagy by the LXR agonist DDA occurred independently of their cytogenetic subgroups and did not distinguish bulk cancer cells from cancer cell progenitors. 44 …”

Exploring the nexus of nuclear receptors in hematological malignancies

“…Further, when DDA was combined with daunorubicin and idarubicin, there was a collaborative increase in cell mortality. Moreover an increased rate of DNA damage was observed when treated with idarubicin alone in AML cells in an LXRβ-dependent manner [ 75 ].…”

Autophagy a Close Relative of AML Biology

“…Mechanistically, DDA triggers autophagy via the activation of the nuclear receptor LXRβ (liver-X-receptorβ) but also via its concomitant action on cholesterol metabolism [ 53 ]. By triggering lethal autophagy, DDA also potentiates the antileukemic activity of anthracyclines (idarubicin or daunorubicin, DNR), which represents, in association with AraC, the gold standard AML therapy [ 54 ].…”