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A photodynamic bifunctional conjugate for prostate cancer: an in vitro mechanistic study

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Summary

Photodynamic therapy (PDT) has drawn considerable attention for its efficacy against certain types of cancers. It shows however limits in the case of deep cancers, favoring tumor recurrence under suboptimal conditions. More insight into the molecular mechanisms of PDT-induced cytotoxicity and cytoprotection is essential to extend and strengthen this therapeutic modality. As PDT induces iNOS/NO in both tumor and microenvironment, we examined the role of nitric oxide (NO) in cytotoxicity and cytoprotection. Our findings show that NO mediates its cellular effects by acting on the NF-κB/YY1/RKIP loop, which controls cell growth and apoptosis. The cytoprotective effect of PDT-induced NO is observed at low NO levels, which activate the pro-survival/anti-apoptotic NF-κB and YY1, while inhibiting the anti-survival/pro-apoptotic and metastasis suppressor RKIP. In contrast, high PDT-induced NO levels inhibit NF-κB and YY1 and induce RKIP, resulting in significant anti-tumor activity. These findings reveal a critical role played by NO in PDT and suggest that the use of bifunctional PDT agents composed of a photosensitizer and a NO-donor could enhance the photo-treatment effect. A successful application of NO in anticancer therapy requires control of its concentration in the target tissue. To address this issue we propose as PDT agent, a bimolecular conjugate called DR2, composed of a photosensitizer (Pheophorbide a) and a non-steroidal anti-androgen molecule capable of releasing NO under the exclusive control of light. The mechanism of action of DR2 in prostate cancer cells is reported and discussed.

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Acknowledgments

The authors are grateful to Dr. Derek Jones, for editorial assistance.

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Authors and Affiliations

  1. Department of Medical and Biological Sciences, University of Udine, Piazzale Kolbe 4, 33100, Udine, Italy

    Valentina Rapozzi, Emilia Della Pietra & Luigi E. Xodo

  2. Institute of Organic Synthesis and Photoreactivity, Italian National Research Council, Via P. Gobetti 101, 40129, Bologna, Italy

    Greta Varchi & Claudia Ferroni

Authors
  1. Valentina Rapozzi
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  2. Greta Varchi
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  3. Emilia Della Pietra
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  4. Claudia Ferroni
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  5. Luigi E. Xodo
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Correspondence to Valentina Rapozzi.

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Conflict of interest

Valentina Rapozzi declares that she has no conflict of interest. Greta Varchi declares that she has no conflict of interest. Emilia Della Pietra declares that she has no conflict of interest. Claudia Ferroni declares that she has no conflict of interest. Luigi Emilio Xodo declares that he has no conflict of interest.

Funding

This work was supported by personal research funds of the Dipartimento di Scienze Mediche e Biologiche (Department of Medical and Biological Sciences), University of Udine, Italy.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Rapozzi, V., Varchi, G., Della Pietra, E. et al. A photodynamic bifunctional conjugate for prostate cancer: an in vitro mechanistic study. Invest New Drugs 35, 115–123 (2017). https://doi.org/10.1007/s10637-016-0396-x

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  • DOI: https://doi.org/10.1007/s10637-016-0396-x

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