Skip to main content

Advertisement

SpringerLink
Log in

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

  • SHORT REPORT
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

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

References

  1. Dohner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373:1136–1152

    Article  Google Scholar 

  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405

    Article  CAS  Google Scholar 

  3. Terwilliger T, Abdul-Hay M (2017) Acute lymphoblastic leukemia: a comprehensive review and 2017 update. Blood Cancer J 7:e577

    Article  CAS  Google Scholar 

  4. Malard F, Mohty M (2020) Acute lymphoblastic leukaemia. Lancet 395:1146–1162

    Article  CAS  Google Scholar 

  5. Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, Hoadley K, Triche TJ Jr, Laird PW, Baty JD, Fulton LL, Fulton R, Heath SE, Kalicki-Veizer J, Kandoth C, Klco JM, Koboldt DC, Kanchi KL, Kulkarni S, Lamprecht TL, Larson DE, Lin L, Lu C, McLellan MD, McMichael JF, Payton J, Schmidt H, Spencer DH, Tomasson MH, Wallis JW, Wartman LD, Watson MA, Welch J, Wendl MC, Ally A, Balasundaram M, Birol I, Butterfield Y, Chiu R, Chu A, Chuah E, Chun HJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Jones S, Karsan A, Lee D, Li HI, Marra MA, Mayo M, Moore RA, Mungall K, Parker J, Pleasance E, Plettner P, Schein J, Stoll D, Swanson L, Tam A, Thiessen N, Varhol R, Wye N, Zhao Y, Gabriel S, Getz G, Sougnez C, Zou L, Leiserson MD, Vandin F, Wu HT, Applebaum F, Baylin SB, Akbani R, Broom BM, Chen K, Motter TC, Nguyen K, Weinstein JN, Zhang N, Ferguson ML, Adams C, Black A, Bowen J, Gastier-Foster J, Grossman T, Lichtenberg T, Wise L, Davidsen T, Demchok JA, Shaw KR, Sheth M, Sofia HJ, Yang L, Downing JR, Eley G (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368:2059–2074

    Article  Google Scholar 

  6. Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Bene MC, De Vos J, Hernandez JM, Hofmann WK, Mills KI, Gilkes A, Chiaretti S, Shurtleff SA, Kipps TJ, Rassenti LZ, Yeoh AE, Papenhausen PR, Liu WM, Williams PM, Foa R (2010) Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol 28:2529–2537

    Article  CAS  Google Scholar 

  7. Machado-Neto JA, de Melo Campos P, Favaro P, Lazarini M, Lorand-Metze I, Costa FF, Olalla Saad ST, Traina F (2014) Stathmin 1 is involved in the highly proliferative phenotype of high-risk myelodysplastic syndromes and acute leukemia cells. Leuk Res 38:251–257

    Article  CAS  Google Scholar 

  8. Machado-Neto JA, Rodrigues Alves APN, Fernandes JC, Coelho-Silva JL, Scopim-Ribeiro R, Fenerich BA, da Silva FB, Scheucher PS, Simoes BP, Rego EM, Traina F (2017) Paclitaxel induces Stathmin 1 phosphorylation, microtubule stability and apoptosis in acute lymphoblastic leukemia cells. Heliyon 3:e00405

    Article  Google Scholar 

  9. Machado-Neto JA, de Melo Campos P, Favaro P, Lazarini M, da Silva Santos Duarte A, Lorand-Metze I, Costa FF, Saad ST, Traina F (2015) Stathmin 1 inhibition amplifies ruxolitinib-induced apoptosis in JAK2V617F cells. Oncotarget 6:29573–29584

    Article  Google Scholar 

  10. Zada AA, Geletu MH, Pulikkan JA, Muller-Tidow C, Reddy VA, Christopeit M, Hiddemann WD, Behre HM, Tenen DG, Behre G (2006) Proteomic analysis of acute promyelocytic leukemia: PML-RARalpha leads to decreased phosphorylation of OP18 at serine 63. Proteomics 6:5705–5719

    Article  CAS  Google Scholar 

  11. Unwin RD, Sternberg DW, Lu Y, Pierce A, Gilliland DG, Whetton AD (2005) Global effects of BCR/ABL and TEL/PDGFRbeta expression on the proteome and phosphoproteome: identification of the Rho pathway as a target of BCR/ABL. J Biol Chem 280:6316–6326

    Article  CAS  Google Scholar 

  12. Jeha S, Luo XN, Beran M, Kantarjian H, Atweh GF (1996) Antisense RNA inhibition of phosphoprotein p18 expression abrogates the transformed phenotype of leukemic cells. Cancer Res 56:1445–1450

    CAS  PubMed  Google Scholar 

  13. Belletti B, Baldassarre G (2011) Stathmin: a protein with many tasks. New biomarker and potential target in cancer. Expert Opin Ther Targets 15:1249–1266

    Article  CAS  Google Scholar 

  14. Machado-Neto JA, Saad ST, Traina F (2014) Stathmin 1 in normal and malignant hematopoiesis. BMB Rep 47:660–665

    Article  Google Scholar 

  15. Shi X, Wang D, Ding K, Lu Z, Jin Y, Zhang J, Pan J (2010) GDP366, a novel small molecule dual inhibitor of survivin and Op18, induces cell growth inhibition, cellular senescence and mitotic catastrophe in human cancer cells. Cancer Biol Ther 9:640–650

    Article  CAS  Google Scholar 

  16. Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Lowenberg B, Bloomfield CD (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:453–474

    Article  Google Scholar 

  17. Carrour TL, Assou S, Tondeur S, Lhermitte L, Lamb N, Reme T, Pantesco V, Hamamah S, Klein B, De Vos J (2010) Amazonia!: An online resource to google and visualize public human whole genome expression data. Open Biotechnol J 4:5–10

    Google Scholar 

  18. Hawkins PC, Skillman AG, Warren GL, Ellingson BA, Stahl MT (2010) Conformer generation with OMEGA: algorithm and validation using high quality structures from the Protein Databank and Cambridge Structural Database. J Chem Inf Model 50:572–584

    Article  CAS  Google Scholar 

  19. Hawkins PC, Skillman AG, Nicholls A (2007) Comparison of shape-matching and docking as virtual screening tools. J Med Chem 50:74–82

    Article  CAS  Google Scholar 

  20. Hanash SM, Strahler JR, Kuick R, Chu EH, Nichols D (1988) Identification of a polypeptide associated with the malignant phenotype in acute leukemia. J Biol Chem 263:12813–12815

    Article  CAS  Google Scholar 

  21. Roos G, Brattsand G, Landberg G, Marklund U, Gullberg M (1993) Expression of oncoprotein 18 in human leukemias and lymphomas. Leukemia 7:1538–1546

    CAS  PubMed  Google Scholar 

  22. Plenker D, Riedel M, Bragelmann J, Dammert MA, Chauhan R, Knowles PP, Lorenz C, Keul M, Buhrmann M, Pagel O, Tischler V, Scheel AH, Schutte D, Song Y, Stark J, Mrugalla F, Alber Y, Richters A, Engel J, Leenders F, Heuckmann JM, Wolf J, Diebold J, Pall G, Peifer M, Aerts M, Gevaert K, Zahedi RP, Buettner R, Shokat KM, McDonald NQ, Kast SM, Gautschi O, Thomas RK, Sos ML (2017) Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med 9:eaah6144

  23. Dar AC, Das TK, Shokat KM, Cagan RL (2012) Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486:80–84

    Article  CAS  Google Scholar 

  24. Liu H, Feng X, Ennis KN, Behrmann CA, Sarma P, Jiang TT, Kofuji S, Niu L, Stratton Y, Thomas HE, Yoon SO, Sasaki AT, Plas DR (2017) Pharmacologic targeting of S6K1 in PTEN-deficient neoplasia. Cell Rep 18:2088–2095

    Article  CAS  Google Scholar 

  25. Yu JX, Craig AJ, Duffy ME, Villacorta-Martin C, Miguela V, Ruiz de Galarreta M, Scopton AP, Silber L, Maldonado AY, Rialdi A, Guccione E, Lujambio A, Villanueva A, Dar AC (2019) Phenotype-based screens with conformation-specific inhibitors reveal p38 gamma and delta as targets for HCC polypharmacology. Mol Cancer Ther 18:1506–1519

    Article  CAS  Google Scholar 

  26. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T, Atkins C, Liu Q, Rabindran S, Kumar R, Hong X, Goetz A, Stanley T, Taylor JD, Sigethy SD, Tomberlin GH, Hassell AM, Kahler KM, Shewchuk LM, Gampe RT (2012) Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem 55:7193–7207

    Article  CAS  Google Scholar 

  27. Stankov K, Popovic S, Mikov M (2014) C-KIT signaling in cancer treatment. Curr Pharm Des 20:2849–2880

    Article  CAS  Google Scholar 

  28. Mahameed M, Wilhelm T, Darawshi O, Obiedat A, Tommy WS, Chintha C, Schubert T, Samali A, Chevet E, Eriksson LA, Huber M, Tirosh B (2019) The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors. Cell Death Dis 10:300

    Article  Google Scholar 

  29. Elkins JM, Fedele V, Szklarz M, Abdul Azeez KR, Salah E, Mikolajczyk J, Romanov S, Sepetov N, Huang XP, Roth BL, Al Haj Zen A, Fourches D, Muratov E, Tropsha A, Morris J, Teicher BA, Kunkel M, Polley E, Lackey KE, Atkinson FL, Overington JP, Bamborough P, Muller S, Price DJ, Willson TM, Drewry DH, Knapp S, Zuercher WJ (2016) Comprehensive characterization of the Published Kinase Inhibitor Set. Nat Biotechnol 34:95–103

    Article  CAS  Google Scholar 

  30. Jiang W, Huang S, Song L, Wang Z (2018) STMN1, a prognostic predictor of esophageal squamous cell carcinoma, is a marker of the activation of the PI3K pathway. Oncol Rep 39:834–842

    CAS  PubMed  Google Scholar 

  31. Li M, Yang J, Zhou W, Ren Y, Wang X, Chen H, Zhang J, Chen J, Sun Y, Cui L, Liu X, Wang L, Wu C (2017) Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer. Br J Cancer 117:974–983

    Article  CAS  Google Scholar 

  32. Pereira JK, Machado-Neto JA, Lopes MR, Morini BC, Traina F, Costa FF, Saad ST, Favaro P (2015) Molecular effects of the phosphatidylinositol-3-kinase inhibitor NVP-BKM120 on T and B-cell acute lymphoblastic leukaemia. Eur J Cancer 51:2076–2085

    Article  CAS  Google Scholar 

  33. Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3:917–921

    Article  CAS  Google Scholar 

  34. Altieri DC (2003) Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 22:8581–8589

    Article  CAS  Google Scholar 

  35. Ong MS, Deng S, Halim CE, Cai W, Tan TZ, Huang RY, Sethi G, Hooi SC, Kumar AP, Yap CT (2020) Cytoskeletal proteins in cancer and intracellular stress: a therapeutic perspective. Cancers (Basel) 12:238

    Article  CAS  Google Scholar 

  36. Pozo K, Bibb JA (2016) The emerging role of Cdk5 in cancer. Trends Cancer 2:606–618

    Article  Google Scholar 

  37. Li WX, Yang MX, Hong XQ, Dong TG, Yi T, Lin SL, Qin XY, Niu WX (2016) Overexpression of gelsolin reduces the proliferation and invasion of colon carcinoma cells. Mol Med Rep 14:3059–3065

    Article  CAS  Google Scholar 

  38. Chen Z, Li K, Yin X, Li H, Li Y, Zhang Q, Wang H, Qiu Y (2019) Lower expression of gelsolin in colon cancer and its diagnostic value in colon cancer patients. J Cancer 10:1288–1296

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP 05508-900, São Paulo, SP, Brazil

    Jorge Antonio Elias Godoy Carlos, Keli Lima, Leticia Veras Costa-Lotufo & João Agostinho Machado-Neto

  2. Medicinal & Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, São Paulo, Brazil

    Andrei Leitão

Authors
  1. Jorge Antonio Elias Godoy Carlos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keli Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leticia Veras Costa-Lotufo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrei Leitão
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. João Agostinho Machado-Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to João Agostinho Machado-Neto.

Ethics declarations

Conflict of interest

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.

Ethical approval

Not applicable. 

Consent to participate

Not applicable.

Consent for publication

Not applicable.  

Code availability

Not applicable.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(PDF 369 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 39, 1139–1149 (2021). https://doi.org/10.1007/s10637-021-01066-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-021-01066-w

Keywords

Search

Navigation