Repeated sub-optimal photodynamic treatments with pheophorbide a induce an epithelial mesenchymal transition in prostate cancer cells via nitric oxide

Pietra, Emilia Della; Simonella, Francesca; Bonavida, Benjamin; Xodo, Luigi E.; Rapozzi, Valentina

doi:10.1016/j.niox.2015.02.005

Cited by 36 publications

(25 citation statements)

References 70 publications

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“…In striking contrast, high-level NO produced by more intense photooxidative pressure resulted in a reversal of these responses: reduced cytoprotection via downregulation of NF-κB, YY1, and SNAIL; upregulation of RKIP; and diminished EMT. 37–39 Although this was not specifically addressed in these studies, 37,38 it is likely that the cytoprotective NO derived initially from iNOS transcription by stress-activated NF-κB and, consistent with our recent evidence, 40 more NO was generated via its positive feedback on NF-κB, although ultimate NO remained at a relatively low (cytoprotective) steady-state level. In contrast, when NO reached a sufficiently high (cytotoxic) level, it would have exerted negative feedback on NF-κB, resulting in downregulation of survival signaling, as described previously.…”

Section: I Nos/no-mediated Resistance To Pdt: In Vitro Studies Wisupporting

confidence: 66%

Role of Endogenous Nitric Oxide in Hyperaggressiveness of Tumor Cells that Survive a Photodynamic Therapy Challenge

Girotti

2016

Crit Rev Oncog

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Many malignant tumors exploit nitric oxide (NO) for a survival, growth, and migration/invasion advantage, and also to withstand the cytotoxic effects of chemo- and radiotherapies. Endogenous NO has also been shown to antagonize photodynamic therapy (PDT), a unique minimally invasive modality involving a photosensitizing (PS) agent, PS-exciting light in the visible- to near-infrared range, and molecular oxygen. The anti-PDT effects of NO were discovered about 20 years ago, but the underlying mechanisms are still not fully understood. More recent studies in the author’s laboratory using breast, prostate, and brain cancer cell lines have shown that inducible NO synthase (iNOS/NOS2) is dramatically upregulated after a PDT challenge using 5-aminolevulinic acid (ALA-) –induced protoporphyrin IX as the PS. The parallel increase in NO resulted not only in a greater resistance to cell killing but also in a striking increase in the growth and migration/invasion rate of surviving cells. These in vitro findings and their recent recapitulation at the in vivo level are discussed in this article, along with how iNOS/NO’s negative effects on PDT can be attenuated by the use of select iNOS inhibitors as PDT adjuvants.

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Section: I Nos/no-mediated Resistance To Pdt: In Vitro Studies Wisupporting

confidence: 66%

Role of Endogenous Nitric Oxide in Hyperaggressiveness of Tumor Cells that Survive a Photodynamic Therapy Challenge

Girotti

2016

Crit Rev Oncog

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“…This loop provided the tool to examine its role and implication in PDT on one hand and its regulation in NO-mediated PDT treatment resulting in either the cytoprotective tumor recurrence or antitumor cytotoxicity. Below briefly, we present our findings that have been recently published [90,91] .…”

Section: No Donors and Pdtmentioning

confidence: 88%

Dual roles of nitric oxide in the regulation of tumor cell response and resistance to photodynamic therapy

2015

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Photodynamic therapy (PDT) against cancer has gained attention due to the successful outcome in some cancers, particularly those on the skin. However, there have been limitations to PDT applications in deep cancers and, occasionally, PDT treatment resulted in tumor recurrence. A better understanding of the underlying molecular mechanisms of PDT-induced cytotoxicity and cytoprotection should facilitate the development of better approaches to inhibit the cytoprotective effects and also augment PDT-mediated cytotoxicity. PDT treatment results in the induction of iNOS/NO in both the tumor and the microenvironment. The role of NO in cytotoxicity and cytoprotection was examined. The findings revealed that NO mediates its effects by interfering with a dysregulated pro-survival/anti-apoptotic NF-κB/Snail/YY1/RKIP loop which is often expressed in cancer cells. The cytoprotective effect of PDT-induced NO was the result of low levels of NO that activates the pro-survival/anti-apoptotic NF-κB, Snail, and YY1 and inhibits the anti-survival/pro-apoptotic and metastasis suppressor RKIP. In contrast, PDT-induced high levels of NO result in the inhibition of NF-kB, Snail, and YY1 and the induction of RKIP, all of which result in significant anti-tumor cytotoxicity. The direct role of PDT-induced NO effects was corroborated by the use of the NO inhibitor, l-NAME, which reversed the PDT-mediated cytotoxic and cytoprotective effects. In addition, the combination of the NO donor, DETANONOate, and PDT potentiated the PDT-mediated cytotoxic effects. These findings revealed a new mechanism of PDT-induced NO effects and suggested the potential therapeutic application of the combination of NO donors/iNOS inducers and PDT in the treatment of various cancers. In addition, the study suggested that the combination of PDT with subtoxic cytotoxic drugs will result in significant synergy since NO has been shown to be a significant chemo-immunosensitizing agent to apoptosis.

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“…Upon photoactivation, Pba induced membrane deterioration, causing release of cytochrome c into the cytoplasm, thus activating the intrinsic apoptotic pathway (Figure 7) [96, 97]. Pba-PDT has also shown promising therapeutic potential in breast cancer [98], bladder cancer [17], prostate cancer [18, 99] and esophageal cancer [100]. …”

Section: Pheophorbidementioning

confidence: 99%

Photosensitizers in prostate cancer therapy

2017

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The search for new therapeutics for the treatment of prostate cancer is ongoing with a focus on the balance between the harms and benefits of treatment. New therapies are being constantly developed to offer treatments similar to radical therapies, with limited side effects. Photodynamic therapy (PDT) is a promising strategy in delivering focal treatment in primary as well as post radiotherapy prostate cancer. PDT involves activation of a photosensitizer (PS) by appropriate wavelength of light, generating transient levels of reactive oxygen species (ROS). Several photosensitizers have been developed with a focus on treating prostate cancer like mTHPC, motexafin lutetium, padoporfin and so on. This article will review newly developed photosensitizers under clinical trials for the treatment of prostate cancer, along with the potential advantages and disadvantages in delivering focal therapy.

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Repeated sub-optimal photodynamic treatments with pheophorbide a induce an epithelial mesenchymal transition in prostate cancer cells via nitric oxide

Cited by 36 publications

References 70 publications

Role of Endogenous Nitric Oxide in Hyperaggressiveness of Tumor Cells that Survive a Photodynamic Therapy Challenge

Role of Endogenous Nitric Oxide in Hyperaggressiveness of Tumor Cells that Survive a Photodynamic Therapy Challenge

Dual roles of nitric oxide in the regulation of tumor cell response and resistance to photodynamic therapy

Photosensitizers in prostate cancer therapy

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