Small Molecule Inhibitors of Microenvironmental Wnt/?-Catenin Signaling Enhance the Chemosensitivity of Acute Myeloid Leukemia.

ABSTRACT: Wnt/?-catenin signaling has been reported in Acute Myeloid leukemia, but little is known about its significance as a prognostic biomarker and drug target. In this study, we first evaluated the correlation between expression levels of Wnt molecules and clinical outcome. Then, we studied-in vitro and in vivo-the anti-leukemic value of combinatorial treatment between Wnt inhibitors and classic anti-leukemia drugs. Higher levels of ?-catenin, Ser675-phospho-?-catenin and GSK-3? (total and Ser 9) were found in AML cells from intermediate or poor risk patients; nevertheless, patients presenting high activity of Wnt/?-catenin displayed shorter progression-free survival (PFS) according to univariate analysis. In vitro, many pharmacological inhibitors of Wnt signalling, i.e., LRP6 (Niclosamide), GSK-3 (LiCl, AR-A014418), and TCF/LEF (PNU-74654) but not Porcupine (IWP-2), significantly reduced proliferation and improved the drug sensitivity of AML cells cultured alone or in the presence of bone marrow stromal cells. In vivo, PNU-74654, Niclosamide and LiCl administration significantly reduced the bone marrow leukemic burden acting synergistically with Ara-C, thus improving mouse survival. Overall, our study demonstrates the antileukemic role of Wnt/?-catenin inhibition that may represent a potential new therapeutics strategy in AML.

SUBMITTER: Takam Kamga P 

PROVIDER: S-EPMC7565567 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature