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

Author(s)

Carlos, Jorge Antonio Elias Godoy ^[1] ; Lima, Keli ^[1] ; Costa-Lotufo, Leticia Veras ^[1] ; Leitao, Andrei ^[2] ; Machado-Neto, Joao Agostinho ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Ave Prof Lineu Prestes 1524, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Med & Biol Chem Grp, Inst Chem Sao Carlos, Sao Paulo - Brazil

• Document type: Journal article
• Source: INVESTIGATIONAL NEW DRUGS; v. 39, n. 4, p. 1139-1149, AUG 2021.
• Web of Science Citations: 0

Abstract

Despite the great advances in the understanding of the molecular basis of acute leukemia, very little of this knowledge has been translated into new therapies. Stathmin 1 (STMN1), a phosphoprotein that regulates microtubules dynamics, is highly expressed in acute leukemia cells and promotes cell cycle progression and proliferation. GDP366 has been described as a STMN1 and survivin inhibitor in solid tumors. 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 (all p < 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 gamma H2AX (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. (AU)

• FAPESP's process: 17/24993-0 - Investigation of Stathmin 1 and microtubule instability in phenotype of hematological neoplasms
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/17177-6 - Integrative approach on the sustainable prospection of marine natural products: from diversity to anticancer compounds
• Grantee: Leticia Veras Costa Lotufo
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 18/15904-6 - Characterization of cysteine protease inhibitors with antineoplastic activity by in silico and cell-based assays coupled with chemical analyses
• Grantee: Andrei Leitão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/19372-9 - Investigation of the effect of potential Stathmin 1 inhibitors obtained by chemoinformatics on the phenotype of acute leukemias
• Grantee: Jorge Antonio Elias Godoy Carlos
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants