Abstract
Simple SummaryRecently, 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.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.
Highlights
The recently discovered Dendrogenin A (DDA) is the first tumor-suppressor of cholesterol origin [1,2]
We recently showed that DDA selectively triggers the lethal autophagy of acute myeloid leukemia (AML) cells in vitro and in vivo through a distinctive mechanism that involves the direct activation of the nuclear receptor transcription factor liver-X-receptor beta (LXRβ) and the inhibition of the cholesterogenic function of D8D7I [3]
Following a 24-hour pretreatment with DDA or vehicle, KG1a cells were incubated with daunorubicin for 30 min, and its intrinsic fluorescence was assessed by flow cytometry after an additional 30 min to allow for drug release
Summary
The recently discovered Dendrogenin A (DDA) is the first tumor-suppressor of cholesterol origin [1,2]. ChEH activity is carried out by two enzymatic subunits involved in cholesterol synthesis, namely the 3β-hydroxysterol-∆8,7-isomerase (D8D7I or EBP) and the 3β-hydroxysterol-∆7-reductase (DHCR7) [6]. We recently showed that DDA selectively triggers the lethal autophagy of AML cells in vitro and in vivo through a distinctive mechanism that involves the direct activation of the nuclear receptor transcription factor liver-X-receptor beta (LXRβ) and the inhibition of the cholesterogenic function of D8D7I [3]. The anti-leukemic activity of DDA was independent of cytogenetic or molecular AML subtypes and prominent in CD34+ CD38− CD123+ AML cells, indicating a broad potential for this compound in the therapy of AML patients. We evaluated the activity of the DDA-anthracycline combination in AML to provide scientific rationale for future clinical trials
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