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

Summary

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 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.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank John De Vos and Tanguy Le Carrour for leading the initiative amazonia! (http://amazonia.transcriptome.eu), thereby providing a tool for analysis of genomic data.

Funding

This study was supported by grant #2019/23864-7, #2017/24993-0, #2018/19372-9, #2018/15904-6, and #2015/17177-6 from the São Paulo Research Foundation (FAPESP), and grant #402587/2016-2 form the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001.

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J.A.E.G.C. designed, executed, and analyzed the experiments and prepared the manuscript. K.L. participated in experiments and analyzed, and prepared the manuscript. L.V.C.-L. provided inputs and participated in the interpretation of data, and edited the manuscript. A.L. designed and executed cheminformatics analyses, participated in the interpretation of data, and edited the manuscript. J.A.M.-N. supervised and participated in the overall design of the study, experiments, and analyzes. All authors read and approved the final manuscript.

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Correspondence to João Agostinho Machado-Neto.

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Jorge Antonio Elias Godoy Carlos declares that he has no conflict of interest. Keli Lima declares that she has no conflict of interest. Leticia Veras Costa-Lotufo declares that she has no conflict of interest. Andrei Leitão declares that he has no conflict of interest. João Agostinho Machado-Neto declares that he has no conflict of interest.

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Carlos, J.A.E.G., Lima, K., Costa-Lotufo, L.V. et al. AD80, a multikinase inhibitor, exhibits antineoplastic effects in acute leukemia cellular models targeting the PI3K/STMN1 axis. Invest New Drugs (2021). https://doi.org/10.1007/s10637-021-01066-w

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Keywords

  • STMN1
  • Acute leukemia
  • GDP366
  • AD80
  • Targeted therapy