AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis

This study identified structural GDP366 analogs and the cellular and molecular mechanisms underlying their suppressive effects on acute leukemia cellular models.STMN1 mRNA levels were higher in AML and ALL patients, independent of risk stratification (allp <  0.001). Cheminformatics analysis identified three structural GDP366 analogs, with AD80 more potent and effective than GSK2606414 and GW768505A. In acute leukemia cells, GDP366 and AD80 reduced cell viability and autonomous clonal growth in a dose- and/or time-dependent manner (p <  0.05) and induced apoptosis and cell cycle arrest (p <  0.05). At the molecular level, GDP366 and AD80 reduced Ki-67 (a proliferation marker) expression and S6 ribosomal protein (a PI3K/AKT/mTOR effector) phosphorylation, and induced PARP1 (an apoptosis marker) cleavage and γH2AX (a DNA damage marker) expression. GDP366 induced STMN1 phosphorylation and survivin expression, while AD80 reduced survivin and STMN1 expression. GDP366 and AD80 modulated 18 of the 84 cytoskeleton regulators-related genes. These results indicated that GDP366 and AD80 reduced the PI3K/STMN1 axis and had cytotoxic effects in acute leukemia cellular models. Our findings further highlight STMN1-mediated signaling as a putative anticancer target for acute leukemia.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research