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

Abstract

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.

Nitric Oxide‐Mediated Resistance to Antitumor Photodynamic Therapy

“…In the case of ALA-PDT, upregulation of the membrane transporter ABCG2 has been demonstrated, which promotes resistance via efflux of newly synthesized PpIX (13). Another key resistance mechanism was discovered in the author's laboratory and involves generation of nitric oxide (NO) by inducible NO synthase (iNOS/ NOS2), which can be upregulated by PDT stress (14,15).…”