Nitric oxide-elicited resistance to anti-glioblastoma photodynamic therapy

Abstract

Glioblastoma multiforme is a highly aggressive primary brain malignancy that resists most conventional chemoand radiotherapeutic interventions. Nitric oxide (NO), a short lived free radical molecule produced by inducible NO synthase (iNOS) in glioblastomas and other tumors, is known to play a key role in tumor persistence, progression, and chemo/radiotherapy resistance. Site-specific and minimally invasive photodynamic therapy (PDT), based on oxidative damage resulting from non-ionizing photoactivation of a sensitizing agent, is highly effective against glioblastoma, but resistance also exists in this case. Studies in the authors' laboratory have shown that much of the latter is mediated by iNOS/NO. For example, when glioblastoma U87 or U251 cells sensitized in mitochondria with 5-aminolevulinic acid-induced protoporphyrin IX were exposed to a moderate dose of visible light, the observed apoptosis was strongly enhanced by an iNOS activity inhibitor or NO scavenger, indicating that iNOS/NO had increased cell resistance to photokilling. Moreover, cells that survived the photochallenge proliferated, migrated, and invaded more aggressively than controls, and these responses were also driven predominantly by iNOS/NO. Photostress-upregulated iNOS rather than basal enzyme was found to be responsible for all the negative effects described. Recognition of NO-mediated hyper-resistance/hyper-aggression in PDT-stressed glioblastoma has stimulated interest in how these responses can be prevented or at least minimized by pharmacologic adjuvants such as inhibitors of iNOS activity or transcription. Recent developments along these lines and their clinical potential for improving anti-glioblastoma PDT are discussed.

Systematic Review and Meta-Analysis of In Vitro Anti-Human Cancer Experiments Investigating the Use of 5-Aminolevulinic Acid (5-ALA) for Photodynamic Therapy

“…The most important candidate that influences the PDT sensitivity is the protein family associated with redox reactions. Oxidative stress-related proteins, such as superoxide dismutase [ 94 ], catalase [ 95 ], and NO synthase [ 96 ], are reported to affect PDT sensitivity. Glutathione and related proteins, such as glutathione peroxidase, glutathione-S-transferase, glutathione transferase omega-1, and glutathione synthase, are also thought to be associated with cell resistance to PDT [ 94 , 97 , 98 ].…”

Therapeutic Influence on Important Targets Associated with Chronic Inflammation and Oxidative Stress in Cancer Treatment

“…The authors of [ 118 ] found a positive correlation between the high iNOS expression and TNM staging of breast cancer. The increased iNOS activity was also found in tissue samples of colorectal cancer [ 119 ], which plays a crucial role in the angiogenesis of this type of neoplasm [ 120 ], in patients with bladder cancer [ 121 ], who are accompanied with high NO levels in tumor tissues, urine, and blood serum [ 52 , 122 ], with pancreatic cancer [ 123 ], non-small-cell lung carcinoma [ 124 ], as well with head and neck squamous carcinoma [ 125 ], glioblastoma [ 126 ], and melanoma [ 127 ]. In addition, it is associated with a poor prognosis in patients.…”

Connexin Hemichannel Activation by S-Nitrosoglutathione Synergizes Strongly with Photodynamic Therapy Potentiating Anti-Tumor Bystander Killing

“…Rapozzi and colleagues proposed a synergistic effect of NO donors and PS to amplify PDT-mediated cytotoxicity [77,78]. However, accumulating evidence reveals that, in sub-optimal PDT treatments, low-level photodynamic stress can induce NO-mediated tumor resistance and pro-survival effects in different cancer types [79,80]. Since the overall amount of produced NO depends on the PS used, irradiation settings, GSNO concentration, and targeted tissue, the parameters for combined treatment must be carefully determined in clinical settings.…”