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

SIMPLE SUMMARY: Recently, several molecules have improved the clinical outcome of acute myeloid leukemia (AML) patients. Despite these recent advances, their prognosis remains poor and new strategies to improve the standard anthracycline and Ara-C-based chemotherapy are needed. We recently published that dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor-suppressor properties, can potentiate the effect of Ara-C to kill AML cells. In this study, we find that DDA can also potentiate anthracycline against AML. The potentiation of Ara-C by DDA is due to a switch from a protective autophagy to a deadly autophagy. Regarding anthracyclines, the potentiation of daunorubicin is caused by the modulation of the efflux by the PgP pump, and that of idarubicin, to an increase in DNA damage and to the induction of a rapid and lethal autophagy. This is caused by rapid modulation of AKT/mTOR and JNK activity, two major pathways involved both in DNA repair and lethal autophagy. 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.