Abstract
Ionizing radiation of specifically targeted cells in a given population is known to elicit pro-death or pro-survival responses in non-targeted bystander cells, which often make no physical contact with the targeted ones. We have recently demonstrated a similar phenomenon for non-ionizing photodynamic therapy (PDT), showing that prostate cancer cells subjected to targeted photodynamic stress stimulated growth and migration of non-stressed, non-contacting bystander cells. Diffusible nitric oxide (NO) generated by stress-upregulated inducible nitric oxide synthase (iNOS) was shown to play a dominant role in these responses. Moreover, target-derived NO stimulated iNOS/NO induction in bystanders, suggesting a NO-mediated feed-forward field effect driven by targeted cells surviving the photodynamic challenge. In this research highlight, we will review these findings and discuss their potential negative implications on clinical PDT outcomes and how these might be mitigated through pharmacologic use of select iNOS inhibitors.
Highlights
Photodynamic therapy (PDT) is a unique, minimally invasive modality for solid tumors that involves a photosensitizing agent (PS), PS-exciting light in the far visible-to-near infrared range, and molecular oxygen [12,13,14]
Using the fluorescent probe DAF-2DA, we found that the level of endogenous nitric oxide (NO) increased after aminolevulinic acid (ALA)/light and that targeting inducible nitric oxide synthase (iNOS) with specific inhibitors (1400W, GW274150) or intercepting NO with a well-known scavenger strongly attenuated this increase [20]
We have presented solid evidence that pre-existing and/or overexpressed iNOS/NO can compromise a widely used anti-cancer therapy, photodynamic therapy (PDT), and possibly stimulate disease progression if the extent of tumor eradication is not great enough
Summary
Ionizing radiation of targeted cells in a given population is known to elicit pro-death or pro-survival responses in non-targeted bystander cells, which often make no physical contact with the targeted ones. We have recently demonstrated a similar phenomenon for non-ionizing photodynamic therapy (PDT), showing that prostate cancer cells subjected to targeted photodynamic stress stimulated growth and migration of non-stressed, non-contacting bystander cells. Diffusible nitric oxide (NO) generated by stress-upregulated inducible nitric oxide synthase (iNOS) was shown to play a dominant role in these responses. Target-derived NO stimulated iNOS/NO induction in bystanders, suggesting a NO-mediated feed-forward field effect driven by targeted cells surviving the photodynamic challenge. We will review these findings and discuss their potential negative implications on clinical PDT outcomes and how these might be mitigated through pharmacologic use of select iNOS inhibitors
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