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.
Newcomb
Elizabeth W
EW
Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. newcoe01@med.nyu.edu
Lukyanov
Yevgeniy
Y
Smirnova
Iva
I
Schnee
Tona
T
Zagzag
David
D
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