Noscapine Crosses the Blood-Brain Barrier and Inhibits Glioblastoma Growth
- Jaren W. Landen1,
- Vincent Hau8,
- Mingshen Wang2,
- Thomas Davis8,
- Brian Ciliax2,
- Bruce H. Wainer3,
- Erwin G. Van Meir456,
- Johnathan D. Glass2,
- Harish C. Joshi1 and
- David R. Archer7
+ Author Affiliations
- Departments of 1 Cell Biology, 2 Neurology, 3 Pathology, 4 Neurosurgery, 5 Winship Cancer Institute, and 6 Hematology/Oncology, and 7 the AFLAC Cancer Center and Blood Disorder Service, Emory University School of Medicine, Atlanta, Georgia; and 8 University of Arizona, Department of Pharmacology, Tucson, Arizona
Full Text: http://clincancerres.aacrjournals.or...0/15/5187.full
Abstract
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 μm) 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 ≤ 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 ≤ 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.