Noscapine induces apoptosis in human glioma cells by an apoptosis-inducing factor-dependent pathway.
Previously, we identified noscapine as a small molecule inhibitor of the hypoxia-inducible factor-1 pathway in hypoxic human glioma cells and human umbilical vein endothelial cells. Noscapine is a nontoxic ingredient in cough medicine currently used in clinical trials for patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia to assess antitumor efficacy. Here, we have evaluated the sensitivity of four human glioma cell lines to noscapine-induced apoptosis. Noscapine was a potent inhibitor of proliferation and inducer of apoptosis. Induction of apoptosis was associated with activation of the c-jun N-terminal kinase signaling pathway concomitant with inactivation of the extracellular signal regulated kinase signaling pathway and phosphorylation of the antiapoptotic protein Bcl-2. Noscapine-induced apoptosis was associated with the release of mitochondrial proteins apoptosis-inducing factor (AIF) and/or cytochrome c. In some glioma cell lines, only AIF release occurred without cytochrome c release or poly (ADP-ribose) polymerase cleavage. Knock-down of AIF decreased noscapine-induced apoptosis. Our results suggest the potential importance of noscapine as a novel agent for use in patients with glioblastoma owing to its low toxicity profile and its potent anticancer activity.
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. newcoe01@med.nyu.edu
Elizabeth W
EW
Newcomb
Yevgeniy
Y
Lukyanov
Iva
I
Smirnova
Tona
T
Schnee
David
D
Zagzag
D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000032:analysis; D056744:Cyclin B1; D045304:Cytochromes c / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009665:Noscapine / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis
D051033:Apoptosis Inducing Factor; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D019253:Proto-Oncogene Proteins c-bcl-2; D009665:Noscapine; D045304:Cytochromes c