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.