Noscapine Crosses the Blood-Brain Barrier and Inhibits Glioblastoma Growth

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 M) 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.

Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death

“…Like many other antimicrotubule agents, noscapine suppresses the dynamics of microtubule assembly and blocks cell cycle progression at mitosis, followed by apoptotic cell death in a wide variety of cancer cell types [18][19][20][21]. Noscapine inhibits the progression of murine lymphoma, melanoma, and human breast tumors implanted in nude mice with little or no toxicity to the kidney, heart, liver, bone marrow, spleen, or small intestine and does not inhibit primary humoral immune responses in mice [18,[22][23][24]. The water solubility and feasibility for oral administration also represent valuable advantages of noscapine over many other antimicrotubule drugs [25][26][27].…”

Drug-resistant T-lymphoid tumors undergo apoptosis selectively in response to an antimicrotubule agent, EM011

“…9 Noscapine has shown a potent anticancer property both in cultured cancer cells and in mouse models of various human cancer types. 8,9,[11][12][13] This agent is currently in phase 1/2 clinical trials for nonHodgkin lymphoma or chronic lymphocytic leukemia refractory to chemotherapy.…”

Development of a Novel Nitro-Derivative of Noscapine for the Potential Treatment of Drug-Resistant Ovarian Cancer and T-Cell Lymphoma

“…This represents an improvement over the taxanes (the microtubule-bundling agents or overpolymerizers) and vincas (the depolymerizers) that cause toxicities in mitotic and postmitotic neurons at elevated doses. Noscapine thus effectively inhibits the progression of various cancer types both in cultured cells and in animal models with no obvious side effects (Ye et al, 1998;Landen et al, 2002Landen et al, , 2004Zhou et al, 2002aZhou et al, , 2003. It is surprising that the apoptosis is much more pronounced in cancer cells than in normal healthy cells (Landen et al, 2002).…”