Glutathione-S-
transferases (
GSTs) are upregulated in
malignant gliomas and contribute to their chemoresistance. The
nitric oxide (NO) donor
PABA/NO (O(2) -{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate) generates NO upon selective enzymatic activation by GST-π-inducing selective
biological effects in
tumors.
Tumor cell killing and chemosensitization were observed in a variety of
tumors after exposure to GST-activated NO donor drugs. In our project, cytotoxic and chemosensitizing effects of
PABA/NO in combination with
carboplatin (
CPT) and
temozolomide (TMZ) were studied in human U87
glioma cells in vitro and in vivo. U87
glioma cells were exposed to
PABA/NO alone or in combination with
CPT or TMZ for 24 hr. Cell viability was assessed by
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 24-hr incubation and 48 hr after
drug removal. The antiproliferative effect of
PABA/NO was assessed in an intracranial U87
glioma nude rat model comparing subcutaneous administration and intratumoral delivery by convection-enhanced delivery.
PABA/NO monotherapy showed a strong dose-dependent growth-inhibitory effect in U87
glioma cells in vitro, and a strong synergistic effect was observed after concomitant treatment with TMZ, but not with
CPT. Systemic and intratumoral
PABA/NO administration significantly reduced cell proliferation, but this did not result in prolonged survival in nude rats with intracranial U87
gliomas.
PABA/NO has potent antiproliferative effects, sensitizes U87
glioma cells to TMZ in vitro and shows some in vivo efficacy. Further studies are still required to consolidate the role of NO donor
therapy in
glioma treatment.