Abstract
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.
Highlights
Dendrogenin A (DDA) is a natural onco-suppressor metabolite at the crossroad between the cholesterol and histamine metabolism [1,2,3,4]
The combinatorial effect on cytotoxicity was assessed by the calculation of a combinatorial index (CI) value across a range of drug concentrations, using the Chou-Talalay method
To evaluate the relevance of these observations in patient tumors, we investigated the efficacy of combination treatments on primary acute myeloid leukemia (AML) cells from three patients that were orthotopically engrafted in NSG (NOD/LtSz-scid IL2Rγc null) mice
Summary
Dendrogenin A (DDA) is a natural onco-suppressor metabolite at the crossroad between the cholesterol and histamine metabolism [1,2,3,4]. Several conjugation products of 5,6-EC with natural amines known to concentrate at the proximity of ChEH were synthesized, and amongst these, DDA emerged as a compound that induced the re-differentiation of cancer cells of various tissue origins into cells with phenotypic characteristics of normal-like cells [1,4,8,9,10]. It was shown that DDA was a metabolite present in various tissues including blood [4]. This pioneering study established that a deregulation of the DDA metabolism occurred in cancers with a decreased DDA level, below pharmacologically active concentrations in tumors and cancer cells compared to normal cells and healthy tissues [4,11]
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