Premium
Upregulation of nitric oxide in tumor cells as a negative adaptation to photodynamic therapy
Author(s) -
Girotti Albert W.
Publication year - 2018
Publication title -
lasers in surgery and medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.888
H-Index - 112
eISSN - 1096-9101
pISSN - 0196-8092
DOI - 10.1002/lsm.22807
Subject(s) - downregulation and upregulation , nitric oxide synthase , photodynamic therapy , nitric oxide , bystander effect , cancer research , cancer cell , in vivo , apoptosis , cancer , biology , pharmacology , chemistry , medicine , immunology , biochemistry , endocrinology , microbiology and biotechnology , organic chemistry , gene
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.© 2018 Wiley Periodicals, Inc.