Growth-inhibitory and chemosensitizing effects of the glutathione-S-transferase-π-activated nitric oxide donor PABA/NO in malignant gliomas†
Evangelos Kogias
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorNadja Osterberg
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorBrunhilde Baumer
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorNikolaos Psarras
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorChristoph Koentges
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorAnna Papazoglou
Department of Stereotactic Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorJoseph E. Saavedra
SAIC-Frederick, NCI at Frederick, Frederick, MD
Search for more papers by this authorLarry K. Keefer
Laboratory of Comparative Carcinogenesis, NCI at Frederick, Frederick, MD
Search for more papers by this authorCorresponding Author
Astrid Weyerbrock
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Tel.: +49-761-270-50070; Fax: +49-761-270-51020
Department of Neurosurgery, University Medical Center Freiburg, Breisacher Strasse 64, D-79106 Freiburg i.Br., GermanySearch for more papers by this authorEvangelos Kogias
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorNadja Osterberg
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorBrunhilde Baumer
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorNikolaos Psarras
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorChristoph Koentges
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorAnna Papazoglou
Department of Stereotactic Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Search for more papers by this authorJoseph E. Saavedra
SAIC-Frederick, NCI at Frederick, Frederick, MD
Search for more papers by this authorLarry K. Keefer
Laboratory of Comparative Carcinogenesis, NCI at Frederick, Frederick, MD
Search for more papers by this authorCorresponding Author
Astrid Weyerbrock
Department of Neurosurgery, University Medical Center Freiburg, Freiburg i.Br., Germany
Tel.: +49-761-270-50070; Fax: +49-761-270-51020
Department of Neurosurgery, University Medical Center Freiburg, Breisacher Strasse 64, D-79106 Freiburg i.Br., GermanySearch for more papers by this authorPublished 2011. This article is a US Government work and, as such, is in the public domain of the United States of America.
Abstract
Glutathione-S-transferases (GSTs) are upregulated in malignant gliomas and contribute to their chemoresistance. The nitric oxide (NO) donor PABA/NO (O2-{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.
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