Abstract
Glioblastoma multiforme is a highly aggressive primary brain malignancy that resists most conventional chemo- and 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.
Highlights
Malignant gliomas such as glioblastoma multiforme (GBM) are among the most aggressive and persistent of all known human tumors[1,2,3]
As with other anti-tumor modalities, e.g., radiotherapy and chemotherapy, photodynamic therapy (PDT) is often confronted with pre-existing or treatment-induced resistance, which can reduce overall efficacy. Exacerbating this is the fact that tumor cells surviving photodynamic stress inevitably acquire a more aggressive phenotype in terms of proliferation and migration/invasion
Endogenous inducible NO synthase (iNOS)/nitric oxide (NO) has been shown to play major role in each of these negative responses, iNOS/NO that is upregulated by PDT stress
Summary
Malignant gliomas such as glioblastoma multiforme (GBM) are among the most aggressive and persistent of all known human tumors[1,2,3]. Bazak et al.[59] observed similar bystander effects with glioblastoma U87 cells and compared them with the effects obtained with prostate PC3, breast MDAMB-231, and melanoma BLM cells, using ALA/light conditions that resulted in uniform kill for all four types (~25%) Under these conditions, bystander proliferation and migration rates increased in proportion to the extent of iNOS upregulation in surviving targeted cells according to the following order: PC3 > MDA-MB-231 > U87 > BLM[59]. For glioblastoma cells in vitro, such agents have been indispensable for identifying pro-growth/migration signaling of endogenous iNOS/NO after an ALA/light challenge[42,48] Might such effects be realized at the clinical level when tumor-repressing PDT is used?
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