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

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. 2018 Dec;36(6):985-998. doi: 10.1007/s10637-018-0590-0.
Elisabetta Bigagli 1,  Cristina Luceri 1,  Maria De Angioletti 2 3,  Konstantin Chegaev 4,  Mario D'Ambrosio 1,  Chiara Riganti 5,  Elena Gazzano 5,  Simona Saponara 6,  Mariangela Longini 7,  Francesca Luceri 8,  Lorenzo Cinci 9
Affiliations

Affiliations

  • 1 Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Section of Pharmacology and Toxicology, University of Florence, Florence, Italy.
  • 2 Cancer Genetics and Gene Transfer Laboratory, Core Research Laboratory, Istituto Toscano Tumori, Florence, Italy.
  • 3 Institute of Chemistry of Organometallic Compounds, CNR, Sesto Fiorentino, Florence, Italy.
  • 4 Department of Drug Science and Technology, University of Turin, Turin, Italy.
  • 5 Department of Oncology, University of Turin, Turin, Italy.
  • 6 Department of Life Sciences, University of Siena, Siena, Italy.
  • 7 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
  • 8 General Laboratory Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy.
  • 9 Department of Neuroscience, Psychology, Drug Research and Child Health - NEUROFARBA - Section of Pharmacology and Toxicology, University of Florence, Florence, Italy. lorenzo.cinci@unifi.it.
PMID: 29607467 DOI: 10.1007/s10637-018-0590-0
Abstract

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.

Keywords

Castration-resistant prostate cancer; Doxorubicin; P-glycoprotein p.

Figures
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  • HY-106399
    Microtubule Polymerization Inhibitor