Noscapine crosses the blood-brain barrier and inhibits glioblastoma growth.
The opium alkaloid noscapine is a commonly used antitussive agent available in Europe, Asia, and South America. Although the mechanism by which it suppresses coughing is currently unknown, it is presumed to involve the central nervous system. In addition to its antitussive action, noscapine also binds to tubulin and alters microtubule dynamics in vitro and in vivo. In this study, we show that noscapine inhibits the proliferation of rat C6 glioma cells in vitro (IC(50) = 100 microm) and effectively crosses the blood-brain barrier at rates similar to the ones found for agents such as morphine and [Met]enkephalin that have potent central nervous system activity (P < or = 0.05). Daily oral noscapine treatment (300 mg/kg) administered to immunodeficient mice having stereotactically implanted rat C6 glioblasoma into the striatum revealed a significant reduction of tumor volume (P < or = 0.05). This was achieved with no identifiable toxicity to the duodenum, spleen, liver, or hematopoietic cells as determined by pathological microscopic examination of these tissues and flow cytometry. Furthermore, noscapine treatment resulted in little evidence of toxicity to dorsal root ganglia cultures as measured by inhibition of neurite outgrowth and yielded no evidence of peripheral neuropathy in animals. However, evidence of vasodilation was observed in noscapine-treated brain tissue. These unique properties of noscapine, including its ability to cross the blood-brain barrier, interfere with microtubule dynamics, arrest tumor cell division, reduce tumor growth, and minimally affect other dividing tissues and peripheral nerves, warrant additional investigation of its therapeutic potential.
Landen
Jaren W
JW
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Hau
Vincent
V
Wang
Mingshen
M
Davis
Thomas
T
Ciliax
Brian
B
Wainer
Bruce H
BH
Van Meir
Erwin G
EG
Glass
Johnathan D
JD
Joshi
Harish C
HC
Archer
David R
DR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000996:Antitussive Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002417:Cattle; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008833:Microcirculation / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009457:Neuroglia / Q000378:metabolism; D009665:Noscapine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D016196:S Phase; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry
D000970:Antineoplastic Agents; D000996:Antitussive Agents; D004396:Coloring Agents; D014404:Tubulin; D009665:Noscapine; D004247:DNA; D001973:Bromodeoxyuridine