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

Abstract

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.

RKIP: A Key Regulator in Tumor Metastasis Initiation and Resistance to Apoptosis: Therapeutic Targeting and Impact

“…Consequently, the modulatory ability of RKIP towards the NF-κB/YY1/Snail circuitry can be considered as one of the underlying mechanisms of RKIP-mediated inhibition of tumor chemo/immuno-resistance [22,30]. Accordingly, agents able to induce RKIP expression or to mimic RKIP function in promoting NF-κB/YY1/Snail suppression are of therapeutic importance for the reversal of acquired therapeutic resistance, including photo-resistance [26,74,123,138,172,175,176,177]. …”

Insights of RKIP-Derived Suppression of Prostate Cancer

“…In PC3 cells treated with PDT, optimized treatment condition led to the production of a high level of NO, which inhibits NFκB and YY1 (Yin Yang 1) transcription factor. As a result, RKIP is upregulated and resulted in cytotoxicity [ 137 , 138 ]. Sub-optimal PDT treatment produces low levels of NO, a condition that activates NFκB-mediated YY1 expression.…”

“…Sub-optimal PDT treatment produces low levels of NO, a condition that activates NFκB-mediated YY1 expression. YY1 subsequently inhibits RKIP, contributing to EMT and the activation of PI3/AKT [ 137 , 138 ]. YY1 promotes PC via EMT development and contributes to therapy resistance [ 139 ].…”

Light-Induced Therapies for Prostate Cancer Treatment

“…Interestingly, our results confirmed that conjugate 11 was selectively uptake by PC cells that over-express the AR, e.g., VCap cells, as respect to those known as not expressing the receptor, i.e., PC3 cancer cells, thus demonstrating the effective in vitro selectivity of the reported system. Moreover, in vitro cytotoxicity studies revealed that compound 11 exerted much higher photo-toxicity when irradiated with white light as respect to red light only, thus demonstrating that besides ROS and 1 O 2 produced by PheoA irradiation, also nitric oxide is released when using a full visible spectrum light source (Rapozzi et al, 2017).…”