Growth inhibition and chemosensitization of exogenous nitric oxide released from NONOates in glioma cells in vitro.
OBJECTIVE
Exogenous nitric oxide (NO) from NO donors has cytotoxic, chemosensitizing, and radiosensitizing effects, and increases vascular permeability and blood flow in tumors. Yet little is known about whether these cytotoxic and chemosensitizing effects can be observed in glioma cells at doses that alter tumor physiological characteristics in vivo and whether these effects are tumor selective.


METHODS
The effect of NO released from proline NONOate, diethylamine NONOate, spermine NONOate, and sodium nitrite on cell proliferation, apoptosis, and chemosensitivity to carboplatin of cultured glioma cells was studied in C6, U87 glioma cells, human glioblastoma cells, and human astrocytes and fibroblasts.


RESULTS
Although proline NONOate failed to induce cell death, the other NO donors induced growth arrest when present in high concentrations (10(-2) M) in all cell lines. Chemosensitization was observed after concomitant incubation with spermine NONOate and carboplatin in C6 and human glioblastoma cells. There is strong evidence that cell death occurs primarily by necrosis and to a lesser degree by apoptosis. The NO doses, which altered tumor physiology in vivo, were not cytotoxic, indicating that NO alters vascular permeability and cell viability in vivo by different mechanisms.


CONCLUSIONS
The authors found that NO-generating agents at high concentrations are potent growth inhibitors and might also be useful as chemosensitizers in glioma cells. These data corroborate the theory that the use of NOgenerating agents may play a role in the multimodal treatment of malignant gliomas but that the NO release must be targeted more specifically to tumor cells to improve selectivity and efficacy.
Weyerbrock
Astrid
A
Department of Neurosurgery, University Medical Center Freiburg, Germany. astrid.weyerbrock@uniklinik-freiburg.de
Baumer
Brunhilde
B
Papazoglou
Anna
A
D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016190:Carboplatin / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004396:Coloring Agents; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D009569:Nitric Oxide / Q000737:chemistry / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D014343:Trypan Blue
D000970:Antineoplastic Agents; D004396:Coloring Agents; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D016190:Carboplatin; D019001:Nitric Oxide Synthase; D014343:Trypan Blue