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MICONIDINE acetate, a new selective and cytotoxic compound with synergic potential, induces cell cycle arrest and apoptosis in leukemia cells

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Summary

Plants are important sources of biologically active compounds and they provide unlimited opportunities for the discovery and development of new drug leads, including new chemotherapeutics. Miconidin acetate (MA) is a hydroquinone derivative isolated from E. hiemalis. In this study we demonstrated that MA was cytotoxic against acute leukemia (AL), solid tumor cells and cancer stem cells, with the strongest effect exhibited against AL. Furthermore, it was non-cytotoxic against non-tumor cells and did not cause significant hemolysis. MA blocks the G2/M phase and causes cytostatic effects, acting in a similar way to dexamethasone by increasing PML expression. The compound also triggered intrinsic and extrinsic apoptosis by modulating Bax, FasR and survivin expression. This led to an extensive mitochondrial damage that resulted in AIF, cytochrome c and endonuclease G release, caspase-3 and PARP cleavage and DNA fragmentation. We have further demonstrated that MA was strongly cytotoxic against neoplastic cells collected from patients with different AL subtypes. Interestingly, MA increased the cytotoxic effect of chemotherapeutics cytarabine and vincristine. This study indicates that MA may be a new agent for AL and highlights its potential as a new source of anticancer drugs.

MA blocks G2/M phase with PML expression and KI67 inhibition, ROS generation and intrinsic and extrinsic apoptosis, leading to mitochondrial damage, caspase 3 and PARP cleavage and DNA fragmentation.

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Fig. 1: Miconidine acetate (MA) chemical structure
Fig. 2: Effect of MA on cancer cells and on normal cells
Fig. 3: Effect of miconidine acetate on cell cycle and apoptosis
Fig. 4: Effect of miconidine acetate on the apoptotic machinery
Fig. 5: Ex vivo and drug-combined experiments

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Acknowledgements

This study was supported by grants and fellowship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) (Brazil). Santos-Silva M.C. is recipient of a Research Fellowship from CNPq (National Counsel of Technological and Scientific Development) (Brazil).

Funding

This study was supported by fellowships from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) (Brazil) and CNPq (National Counsel of Technological and Scientific Development) (Brazil) n° 306682/2015–0.

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Authors and Affiliations

  1. Experimental Oncology and Hemopathies Laboratory, Clinical Analysis Department, Federal University of Santa Catarina, Florianópolis, SC, CEP: 88040-900, Brazil

    Mariana Franzoni Maioral, Natália Marceli Stefanes, Álisson Bigolin & Maria Cláudia Santos-Silva

  2. Post-Graduation Program in Pharmacy, Health Science Center, Federal University of Santa Catarina, Florianópolis, SC, CEP: 88040-900, Brazil

    Mariana Franzoni Maioral, Natália Marceli Stefanes, Álisson Bigolin, Gabriele Andressa Zatelli, Ana Cláudia Philippus, Miriam de Barcellos Falkenberg & Maria Cláudia Santos-Silva

  3. Laboratório de Oncologia Experimental e Hemopatias (LOEH), Departamento de Análises Clínicas, Centro de Ciências da Saúde - Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil

    Maria Cláudia Santos-Silva

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  1. Mariana Franzoni Maioral
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  2. Natália Marceli Stefanes
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  3. Álisson Bigolin
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  4. Gabriele Andressa Zatelli
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  6. Miriam de Barcellos Falkenberg
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  7. Maria Cláudia Santos-Silva
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Contributions

Mariana Maioral: Cell viability, FACS and WB experiments; manuscript writing.

Natália Stefanes: Synergic experiments with chemotherapeutics; manuscript writing.

Álisson Bigolin: Cell viability experiments; manuscript writing.

Gabriele Zatelli: Compound extraction, isolation and identification; manuscript writing.

Ana Philippus: Compound extraction, isolation and identification; manuscript writing.

Miriam de Barcellos Falkenberg: Manuscript review; experimental supervision.

Maria Cláudia Santos-Silva: Manuscript review; experimental supervision.

Corresponding author

Correspondence to Maria Cláudia Santos-Silva.

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Conflict of interest

Author A (Mariana Franzoni Maioral) declares that she has no conflict of interest. Author B (Natália Marceli Stefanes) declares that she has no conflict of interest. Author C (Álisson Bigolin) declares that he has no conflict of interest. Author D (Gabriele Andressa Zatelli) declares that she has no conflict of interest. Author E (Ana Cláudia Philippus) declares that she has no conflict of interest. Author F (Miriam de Barcellos Falkenberg) declares that she has no conflict of interest. Author G (Maria Cláudia Santos-Silva) declares that she has no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants have been conducted with the ethical approval of relevant bodies and that such approvals are acknowledged within the manuscript (Medical Ethics Committee CEPSH n°746.486/2014).

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Informed consent was obtained from all individual participants included in the study.

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Maioral, M.F., Stefanes, N.M., Bigolin, Á. et al. MICONIDINE acetate, a new selective and cytotoxic compound with synergic potential, induces cell cycle arrest and apoptosis in leukemia cells. Invest New Drugs 37, 912–922 (2019). https://doi.org/10.1007/s10637-018-0694-6

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