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New NO- and H2S-releasing doxorubicins as targeted therapy against chemoresistance in castration-resistant prostate cancer: in vitro and in vivo evaluations

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Summary

Chemotherapy for castration-resistant prostate cancer (CRPC) is only temporarily effective due to the onset of chemoresistance. We investigated the efficacy of NO- and H2S-releasing doxorubicins (NitDox and H2SDox) in overcoming drug resistance and evaluated their safety. New and innovative NO- and H2S-releasing doxorubicins (NitDox and H2SDox) showed a good intracellular accumulation and high cytotoxic activity in vitro in an androgen-independent and doxorubicin-resistant DU-145 prostate cancer cell line. Nude mice were subcutaneously injected with 4*106 DU-145 cells and treated once a week for 3 weeks with 5 mg/kg doxorubicin, NitDox, H2SDox or vehicle, i.p. Animal weight, tumor volume, intra-tumoral drug accumulation, apoptosis and the presence of nitrotyrosine and sulfhydryl (SH) groups within the tumor, were evaluated. Cardiotoxicity was assessed by measuring troponin plasma levels and the left ventricular wall thickness. In vivo, NitDox and H2SDox accumulated inside the tumors, significantly reduced tumor volumes by 60%, increased the percentage of apoptotic cells in both the inner and the outer parts of the tumors and the presence of nitrotyrosine and SH groups. Doxorubicin treatment was associated with reduced body weight and cardiotoxicity. On the contrary, NitDox and H2SDox were well tolerated and had a better safety profile. Combining efficacy with reduced cardiovascular side effects, NitDox and H2SDox are promising novel therapeutic agents for reversing chemoresistance in CRCP.

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Fig. 1
Fig. 2
Fig. 3: High-throughput screening of cancer cell lines treated with NitDox
Fig. 4: High-throughput screening of cancer cell lines treated with H2SDox
Fig. 5: Cell viability, necrotic cell death, apoptosis and drug accumulation in DU-145 cells
Fig. 6: Survival, body weight curves and tumor volumes
Fig. 7: Intratumoral drug uptake
Fig. 8: Percentage of apoptotic cells in tumors
Fig. 9: Nitrotyrosine residues and SH group detection in tumors
Fig. 10: Left ventricular wall thickness

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Acknowledgements

The authors are very grateful to Prof. Piero Dolara for critical reading of the manuscript and his useful suggestions.

Funding

This work was supported by Ministry of Education, University and Research (MIUR) by the grant FIRB 2012 code RBFR12SOQ1: “Optimization of oncology therapy: novel drugs affecting multidrug resistance”; Italian Association for Cancer Research (IG15232).

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Author notes

  1. Elisabetta Bigagli and Cristina Luceri contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA – Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

    Elisabetta Bigagli, Cristina Luceri, Mario D’Ambrosio & Lorenzo Cinci

  2. Cancer Genetics and Gene Transfer Laboratory, Core Research Laboratory, Istituto Toscano Tumori, Florence, Italy

    Maria De Angioletti

  3. Institute of Chemistry of Organometallic Compounds, CNR, Sesto Fiorentino, Florence, Italy

    Maria De Angioletti

  4. Department of Drug Science and Technology, University of Turin, Turin, Italy

    Konstantin Chegaev

  5. Department of Oncology, University of Turin, Turin, Italy

    Chiara Riganti & Elena Gazzano

  6. Department of Life Sciences, University of Siena, Siena, Italy

    Simona Saponara

  7. Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy

    Mariangela Longini

  8. General Laboratory Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy

    Francesca Luceri

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  1. Elisabetta Bigagli
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Correspondence to Lorenzo Cinci.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal care and experimental protocols were approved by the Italian Ministry of Health with authorization number 49/2016-PR 21/01/2016.

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Supplementary Figure 1

GI50 of cancer cell lines treated with doxorubicin. GI50 was calculated as reported in the Materials and Methods section, on 60 cancer cell lines of the NCI panel, after 48 h treatment with 10−4 to 10−8 M doxorubicin (here indicated as compound 123,127). (GIF 20 kb)

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Bigagli, E., Luceri, C., De Angioletti, M. et al. New NO- and H2S-releasing doxorubicins as targeted therapy against chemoresistance in castration-resistant prostate cancer: in vitro and in vivo evaluations. Invest New Drugs 36, 985–998 (2018). https://doi.org/10.1007/s10637-018-0590-0

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