Upregulation of nitric oxide in tumor cells as a negative adaptation to photodynamic therapy.

One of the advantages of PDT is that it can often circumvent tumor resistance to chemotherapeutic agents such as cisplatin and doxorubicin. However, pre-existing and acquired resistance to PDT has also been demonstrated. One type of resistance, which involves nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS/NOS2) in tumor cells, was discovered in the author's laboratory. When subjected to a 5-aminolevulinic acid (ALA)-based photodynamic challenge, several cancer lines, including breast, prostate, and glioma, underwent intrinsic apoptosis that could be substantially enhanced by iNOS enzymatic inhibitors or a NO scavenger, implying iNOS/NO-mediated resistance. In most cases, iNOS was significantly upregulated by the challenge and this appeared to be more important in the hyper-resistance than pre-existing enzyme. Of added importance was our observation that cells surviving ALA/light treatment typically exhibited a more aggressive phenotype, proliferating and migrating/invading more rapidly than controls in iNOS/NO-dependent fashion. Most of these in vitro PDT findings have recently been confirmed at the in vivo level, using a human breast tumor xenograft model. We have also shown that upregulated iNOS in PDT-targeted cells can elicit a pro-growth/migration response in non-targeted bystander cells, NO again playing a key role. Post-PDT resistance and potentially dangerous hyper-aggressiveness can be attenuated by inhibitors of iNOS enzymatic activity, some of which have seen pharmacologic use in non-cancer or PDT settings. These various aspects of PDT antagonism by tumor iNOS/NO and how they might be overcome will be discussed in this review. Lasers Surg. Med. 50:590-598, 2018.