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The Schiff base hydrazine copper(II) complexes induce apoptosis by P53 overexpression and prevent cell migration through protease-independent pathways

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Abstract

Although chemotherapy has increased the life expectancy of cancer patients, its toxic side effects remain a major challenge. Recently, organometallic compounds, such as Schiff base copper complexes, have become promising candidates for next-generation anticancer drugs owing to their unique anticancer activities. In this study, binuclear copper(II) complex-1 and mononuclear copper(II) complex-2 were examined to analyze their anticancer mechanisms further. For this purpose, a viability test, flow cytometry analysis of apoptosis and the cell cycle, migration assay, and gene expression analysis were performed. According to our results, complex-1 was more cytotoxic than complex-2 at 24/48-h intervals. Our findings also demonstrated that both complexes induced apoptosis at IC50 concentrations and arrested the cell cycle at the G1-S checkpoint. However, complex-1 accelerates cell cycle arrest at the sub-G0/G1 phase more than complex-2 does. Furthermore, gene expression analysis showed that only complex-1 induces the expression of p53. Interestingly, both complexes induced Bcl-2 overexpression. However, they did not affect MMP-13 expression. More interestingly, both complexes inhibited cell migration in different ways, including amoeboid and collective, by recruiting protease-independent pathways. This study confirmed that adding several metal cores and co-ligands increased the activity of the complex. It also appeared that Cu-containing complexes could prevent the migration of cancer cells through protease-independent pathways, which can be used for novel therapeutic purposes.

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Funding

This work was supported by the Ardabil University of Medical Sciences. Funding organization had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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  1. Yasin Panahi

    Present address: Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, 5816753464, Iran

Authors and Affiliations

  1. Deputy of Research & Technology, Ardabil University of Medical Sciences, Ardabil, Iran

    Vahid Asghariazar

  2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Amini & Behzad Baradaran

  3. Department of Pharmacology & Toxicology, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Zahra Pirdel & Yasin Panahi

  4. Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran

    Roghayeh Fekri & Asadollah Asadi

  5. Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran

    Kazem Nejati-Koshki

  6. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Behzad Baradaran

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Contributions

All authors contributed to the study's conception and design. Y.P. performed material preparation, data collection, and analysis. The experiments were set up and carried out by V.A., M.A., Z.P., and R.F. The previous version of the manuscript was edited by A.A., K.N., and B.B. and commented on by all authors. Finally, Y.P. wrote and revised the entire manuscript for submission. All authors read and approved the final version of the manuscript for submission.

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Correspondence to Yasin Panahi.

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Ethical approval for this study was granted by the Ardabil University of Medical Sciences Ethics Committee Reference Number IR.ARUMS.REC.1399.295.

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Asghariazar, V., Amini, M., Pirdel, Z. et al. The Schiff base hydrazine copper(II) complexes induce apoptosis by P53 overexpression and prevent cell migration through protease-independent pathways. Med Oncol 40, 271 (2023). https://doi.org/10.1007/s12032-023-02150-2

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