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such tumors are typically more sensitive to oxidative pressure than normal counterparts [19,20] . In many
tumor cells, including glioma cells, NO can activate pro-survival signaling pathways by modifying effector
proteins such as soluble guanyl cyclase (sGC), hypoxia-inducible fctor-1α (HIF-1α), extracellular signal-
regulated kinases-1 and -2 (ERK-1/2), epidermal growth factor receptor (EGFR), or protein kinase-B (Akt)
via phosphoinositide-3-kinase (PI3K) [22-25] . Such modification may occur via S-nitrosation of thiol groups
[26]
on specific cysteine residues . In this case, NO itself does not react usually, but rather some oxidized
form of NO such as nitrosyl anhydride (N O ) or a trans-nitrosating species such as S-nitroso-glutathione
2
3
(GSNO) [26-28] . iNOS-derived NO from myeloid-derived suppressor cells (MDSCs) may also benefit
[29]
malignant tumors by inactivating anti-tumor cytotoxic T-cells . In this case, the cytotoxic agent is a strong
−
NO-derived oxidant such as ONOO . There is increasing evidence that endogenous NO at low levels (e.g.,
from tumor cells themselves or proximal vascular cells) can also increase tumor resistance to ionizing
radiation or chemotherapeutic agents such as cisplatin and docetaxel . This has been amply demonstrated
[30]
[31]
for malignant gliomas, glioma stem cells (GSCs) in these tumors exhibiting much of this resistance .
Significant resistance to non-ionizing photodynamic therapy can also develop, which is discussed after
basic principles of this treatment are described.

ANTI-TUMOR PHOTODYNAMIC THERAPY: SOME BASIC PRINCIPLES
Photodynamic therapy (PDT) was introduced about 45 years ago as a novel means of selectively
eradicating a variety of solid malignancies, many of which are refractory to conventional chemotherapy
or radiotherapy [32-34] . PDT is a minimally invasive modality which typically exhibits little, if any, off-target
cytotoxicity. Classical PDT consists of three operating components: (1) an administered photosensitizing
agent (PS); (2) PS photoexcitation by non-ionizing radiation, typically in the far visible to near-infrared
wavelength range; and (3) molecular oxygen [32-34] . For many tumors, including glioblastomas, light can
be delivered interstitially via fiber optic networks, making this approach highly selective for the tumor
target [33,34] . Without photoactivation, most PS are innocuous to tumor cells as well as normal cells, which
distinguishes these PS from many chemotherapeutic agents, e.g., platinum-based drugs. In a common
photodynamic reaction (Type II process), ground state PS is excited to a meta-stable singlet state, which
crosses over to a longer-lived triplet excited state. The latter then transfers energy to ground-state O , giving
2
singlet molecular oxygen ( O ), a cytotoxic reactive oxygen species (ROS) [33,34] . For some PS, more complex
1
2
electron or hydrogen transfer may occur (Type I process), resulting in formation of free radical or free
−
radical-derived ROS, e.g., superoxide (O ·), hydroxyl radical (HO·), and hydrogen peroxide (H O ). Similar
2
2
2
1
to O , these ROS can kill tumor cells by oxidizing vital molecules (proteins, lipids, and nucleic acids) and
2
[34]
activating death signaling pathways . In 1995, Photofrin®, a hematoporphyrin oligomer, became the first
[32]
PS to be FDA-approved for anti-tumor PDT, esophageal malignancies being treated initially . Since then,
PDT with Photofrin® and other PSs has been used to combat numerous other malignancies, including
prostate, breast, cervical, head and neck, and brain (gliomas) [33,34] . PDT is now considered one of the most
promising alternatives to radiotherapy and chemotherapy for treating highly aggressive brain malignancies
such as glioblastoma [8-10,35,36] . One explanation for this pertains to distinct subcellular targets. PDT usually
damages cytoplasmic organelles (mitochondria, lysosomes, and endoplasmic reticulum), whereas
radiotherapy (X-rays and γ-rays) and chemotherapy (e.g., with platinum-based drugs) damage nuclear
DNA . As a result, any constitutive or acquired resistance to chemo- or radiotherapy may not apply when
[37]
PDT is used. Moreover, PDT elicits a robust anti-tumor immune response, and this provides an additional
[38]
advantage by eliminating cells that might withstand a PDT challenge .
Unlike Photofrin® and other PSs that are administered as such, pro-sensitizers have been developed which
are converted to active PS after being administered. One important example is 5-aminolevulinic acid (ALA),
which enters tumor cells via an amino acid transporter and is metabolized to active PS, protoporphyrin IX
(PpIX), via the heme biosynthetic pathway [Figure 1], the PpIX accumulating initially in mitochondria [39-41] .
This pathway is typically more active in malignant cells (e.g., glioblastomas) than normal counterparts,