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Pharmacological assessment of the antineoplastic and immunomodulatory properties of a new spiroindolone derivative (7’,8’-Dimethoxy-1’,3’-dimethyl-1,2,3’,4’-tetrahydrospiro[indole-3,5’-pyrazolo[3,4-c]isoquinolin]-2-one) in chronic myeloid leukemia

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Abstract

The discovery and development of effective novel compounds is paramount in oncology for improving cancer therapy. In this study, we developed a new derivative of spiroindolone (7’,8’-Dimethoxy-1’,3’-dimethyl-1,2,3’,4’-tetrahydrospiro[indole-3,5’- pyrazolo[3,4-c]isoquinolin]-2-one) and evaluated its anticancer- and immunomodulatory potential in a vitro model of chronic leukemia. We utilized the chronic leukemia cell line K562, as well as non-cancerous peripheral blood mononuclear cells (PBMC) and Vero cells (kidney epithelium of Cercopithecus aethiops). We assessed the cytotoxicity of the compound using the MTT assay, and performed cell cycle assays to determine its impact on different stages of the cell cycle. To evaluate its antineoplastic activity, we conducted a colony formation test to measure the effect of the compound on the clonal growth of cancer cells. Furthermore, we evaluated the immunomodulatory activity of the compound by measuring the levels of pro and anti-inflammatory cytokines. The study findings demonstrate that the spiroindolone-derived compound exerted noteworthy cytotoxic effects against K562 cells, with an IC50 value of 25.27 µg/mL. Additionally, it was observed that the compound inhibited the clonal proliferation of K562 cells while displaying minimal toxicity to normal cells. The compound exhibited its antiproliferative activity by inducing G2/M cell cycle arrest, preventing the entry of K562 cells into mitosis. Notably, the compound demonstrated an immunomodulatory effect by upregulating the production of cytokines IL-6 and IL-12/23p40. In conclusion, the spiroindolone-derived compound evaluated in this study has demonstrated significant potential as a therapeutic agent for the treatment of chronic myeloid leukemia. Further investigations are warranted to explore its clinical applications.

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Data availability

Data obtained and analyzed in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Acknowledgments to the Institute of Chemical Institute of Ukraine, to the Horizon2020-MSCA-RISE-2016-734759 project, acronym VAHVISTUS, to the Research Support Foundation of the State of Amazonas (FAPEAM) e to the Hospital Foundation of Hematology and Hemotherapy of the Amazon (FHEMOAM).

Funding

This research was funded by the Research Support Foundation of the State of Amazonas (FAPEAM) (CT&I ÁREAS PRIORITÁRIAS #01.02.016301.03422/2021-03), the Coordination of Improvement of Higher Education Personnel (CAPES) (Finance code—PROCAD AMAZÔNIA 88881.200581/201801) and the Horizon2020-MSCA-RISE-2016-734759 project, acronym VAHVISTUS.

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  1. The authors Carlos Eduardo de Castro Alves and Serge L. Bogza contribute equally

Authors and Affiliations

  1. Post-Graduate Program in Basic and Applied Immunology, Institute of Biological Science, Federal University of Amazonas, Manaus, 69077-000, AM, Brazil

    Carlos Eduardo de Castro Alves, Regiane Costa de Oliveira, Renata Galvão de Azevedo & Gemilson Soares Pontes

  2. Laboratory of Virology and Immunology, National Institute of Amazonian Research (INPA), Manaus, 69067- 375, AM, Brazil

    Carlos Eduardo de Castro Alves, Larissa Raquel Silva Maciel & Gemilson Soares Pontes

  3. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Academician Kukhar str. 5, Kyiv, 02094, Ukraine

    Serge L. Bogza, Nathalie Bohdan & Alexander B. Rozhenko

  4. National Technical University of Ukraine ‘Igor Sikorsky Kyiv Polytechnic Institute’, Beresteiskyi prosp. 37, Kyiv, 03056, Ukraine

    Alexander B. Rozhenko

  5. Post-Graduate Program in Hematology, Foundation of Hematology and Hemotherapy of Amazonas, The State University of Amazon, Manaus, 69050-010, AM, Brazil

    Alice de Freitas Gomes, Anamika Dhyani & Gemilson Soares Pontes

  6. Materials Chemistry Division, Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, Helsinki, 00560, Finland

    Andriy Grafov

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Contributions

Carlos Eduardo de C. Alves: project administration, manuscript writing, writing - review and editing, methodology, investigation, data analysis. Serge L. Bogza, Nathalie Bohdan and Alexander B. Rozhenko: compound design and synthesis, manuscript review. Alice de Freitas Gomes: methodology, investigation, formal analysis. Regiane Costa de Oliveira: methodology, investigation, formal analysis, writing - review. Renata Galvão de Azevedo and Larissa Raquel Silva: methodology, investigation, formal analysis. Anamika Dhyani: methodology, investigation, formal analysis, provision of resources for the study. Andriy Grafov: compound design and synthesis, provision of resources for the study. Gemilson Soares Pontes: project administration, conceptualization, funding acquisition, investigation, writing - review and editing, formal analysis. All authors read and approved the final manuscript.

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Correspondence to Gemilson Soares Pontes.

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Approval for the utilization of human PBMCs was granted by the Research Ethics Committee (REC) of the Foundation of Hematology and Hemotherapy Foundation of Amazonas State (HEMOAM), Brazil (approval number: 3.138.343; approved on February 8, 2019).

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de Castro Alves, C.E., Bogza, S.L., Bohdan, N. et al. Pharmacological assessment of the antineoplastic and immunomodulatory properties of a new spiroindolone derivative (7’,8’-Dimethoxy-1’,3’-dimethyl-1,2,3’,4’-tetrahydrospiro[indole-3,5’-pyrazolo[3,4-c]isoquinolin]-2-one) in chronic myeloid leukemia. Invest New Drugs 41, 629–637 (2023). https://doi.org/10.1007/s10637-023-01382-3

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