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Girotti et al. J Cancer Metastasis Treat 2020;6:52 Journal of Cancer
DOI: 10.20517/2394-4722.2020.107 Metastasis and Treatment

Review Open Access

Negative effects of tumor cell nitric oxide on anti-
glioblastoma photodynamic therapy

Albert W. Girotti , Jonathan M. Fahey , Witold Korytowski 2
1
1
1 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
2 Department of Biophysics, Jagiellonian University, Krakow 30-387, Poland.
Correspondence to: Dr. Albert W. Girotti, Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank
Road, Milwaukee, Wisconsin, 53226-3548, United States. E-mail: agirotti@mcw.edu
How to cite this article: Girotti AW, Fahey JM, Korytowski W. Negative effects of tumor cell nitric oxide on anti-glioblastoma
photodynamic therapy. J Cancer Metastasis Treat 2020;6:52. http://dx.doi.org/10.20517/2394-4722.2020.107
Received: 25 Sep 2020 Accepted: 1 Dec 2020 Published: 24 Dec 2020

Academic Editor: Lombardi Giuseppe Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract
Glioblastomas are highly aggressive brain tumors that can persist after exposure to conventional chemotherapy
or radiotherapy. Nitric oxide (NO) produced by inducible NO synthase (iNOS/NOS2) in these tumors is known
to foster malignant cell proliferation, migration, and invasion as well as resistance to chemo- and radiotherapy.
Minimally invasive photodynamic therapy (PDT) sensitized by 5-aminolevulinic acid (ALA)-induced protoporphyrin
IX (PpIX) is a highly effective anti-glioblastoma modality, but it is also subject to NO-mediated resistance. Studies
by the authors have revealed that glioblastoma U87 and U251 cells use endogenous iNOS/NO to not only resist
photokilling after an ALA/light challenge, but also to promote proliferation and migration/invasion of surviving cells.
Stress-upregulated iNOS/NO was found to play a major role in these negative responses to PDT-like treatment. Our
studies have revealed a tight network of upstream signaling events leading to iNOS induction in photostressed cells
and transition to a more aggressive phenotype. These events include activation or upregulation of pro-survival/
pro-expansion effector proteins such as NF-κB, phosphoinositide-3-kinase (PI3K), protein kinase-B (Akt), p300,
Survivin, and Brd4. In addition to this upstream signaling and its regulation, pharmacologic approaches for directly
suppressing iNOS at its activity vs. transcriptional level are discussed. One highly effective agent in the latter
category is bromodomain and extra-terminal (BET) inhibitor, JQ1, which was found to minimize iNOS upregulation
in photostressed U87 cells. By acting similarly at the clinical level, a BET inhibitor such as JQ1 should markedly
improve the efficacy of anti-glioblastoma PDT.

Keywords: Glioblastoma, photodynamic therapy, nitric oxide, inducible NO synthase

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
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