Antagonistic Effects of Endogenous Nitric Oxide in a Glioblastoma Photodynamic Therapy Model. Photochem Photobiol 2016 Nov;92(6):842-853
Date
09/09/2016Pubmed ID
27608331Pubmed Central ID
PMC5161550DOI
10.1111/php.12636Scopus ID
2-s2.0-84991677078 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
Gliomas are aggressive brain tumors that are resistant to conventional chemotherapy and radiotherapy. Much of this resistance is attributed to endogenous nitric oxide (NO). Recent studies revealed that 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) has advantages over conventional treatments for glioblastoma. In this study, we used an in vitro model to assess whether NO from glioblastoma cells can interfere with ALA-PDT. Human U87 and U251 cells expressed significant basal levels of neuronal NO synthase (nNOS) and its inducible counterpart (iNOS). After an ALA/light challenge, iNOS level increased three- to fourfold over 24 h, whereas nNOS remained unchanged. Elevated iNOS resulted in a large increase in intracellular NO. Extent of ALA/light-induced apoptosis increased substantially when an iNOS inhibitor or NO scavenger was present, implying that iNOS/NO was acting cytoprotectively. Moreover, cells surviving a photochallenge exhibited a striking increase in proliferation, migration and invasion rates, iNOS/NO again playing a dominant role. Also observed was a large iNOS/NO-dependent increase in matrix metalloproteinase-9 activity, decrease in tissue inhibitor of metalloproteinase-1 expression and increase in survivin and S100A4 expression, each effect being consistent with accelerated migration/invasion as a prelude to metastasis. Our findings suggest introduction of iNOS inhibitors as pharmacologic adjuvants for glioblastoma PDT.
Author List
Fahey JM, Emmer JV, Korytowski W, Hogg N, Girotti AWAuthor
Neil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adjuvants, PharmaceuticAminolevulinic Acid
Animals
Apoptosis
Cell Line, Tumor
Cell Survival
Glioblastoma
Humans
Nitric Oxide
Nitric Oxide Synthase Type II
Photochemotherapy