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. 1998 Feb 17;95(4):1601-6.
doi: 10.1073/pnas.95.4.1601.

Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells

K Ye  1 , Y Ke, N Keshava, J Shanks, J A Kapp, R R Tekmal, J Petros, H C Joshi
Affiliations

Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells

K Ye et al. Proc Natl Acad Sci U S A. .

Abstract

An alkaloid from opium, noscapine, is used as an antitussive drug and has low toxicity in humans and mice. We show that noscapine binds stoichiometrically to tubulin, alters its conformation, affects microtubule assembly, and arrests mammalian cells in mitosis. Furthermore, noscapine causes apoptosis in many cell types and has potent antitumor activity against solid murine lymphoid tumors (even when the drug was administered orally) and against human breast and bladder tumors implanted in nude mice. Because noscapine is water-soluble and absorbed after oral administration, its chemotherapeutic potential in human cancer merits thorough evaluation.

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Figures

Figure 1
Figure 1
Chemical structures of noscapine.
Figure 2
Figure 2
Noscapine arrests HeLa cells at M phase. Immunofluorescent micrographs showing microtubule arrays (A and C) and DNA (B and D) in noscapine-treated HeLa cells (A and B) and control cells (C and D). (Bar = 15 μm.)
Figure 3
Figure 3
Flow cytometric analysis of noscapine-treated HeLa cells at 0 (A), 12 (B), 24 (C), 36 (D), and 48 (E) h after noscapine treatment.
Figure 4
Figure 4
Noscapine initiates apoptosis. (A) Progressive DNA degradation with increasing time of noscapine treatment. Lanes 2–6 contain 10 μg of DNA isolated from cells treated with 20 μM noscapine for 0 h, 4 h, 8 h, 12 h, and 24 h, respectively. Lane 1 contains molecular size markers. (B) Number of apoptotic cells with increasing time of incubation in 20 μM noscapine or the vehicle solution (DMSO). Cells with three or more visible chromatin masses were considered apoptotic. Each value represents the mean range of duplicate determinations of 400 cells. (C and D) Apoptotic cells revealed by using TUNEL assay. Apoptotic nuclei stained brown (arrowhead). (Bar = 30 μm.)
Figure 5
Figure 5
Inhibition of tumor growth with noscapine. Tumor weights from each group were averaged and compared with the control group. ∗, Results are significantly different when compared with control group (P < 0.01).
Figure 6
Figure 6
Effect of noscapine on human breast tumor growth. (A) Reduction of tumor volume during the treatment period. (B) The average tumor weight. (C and D) Apoptotic cells (arrows) in untreated control and noscapine-treated cells, respectively. (Bar = 35 μm.)
Figure 7
Figure 7
Noscapine induces conformational change on binding tubulin and alters microtubule assembly. (A) Fluorescence quenching of tubulin by noscapine. (B) Scatchard plot showing an apparent dissociation constant (Kd) of 1.86 ± 0.34 × 10−6 M and an stoichiometry of 0.95 ± 0.02 noscapine molecule per complex of tubulin subunit. (Inset) Saturation of the noscapine-induced quenching in tubulin fluorescence intensity. (C) CD spectra of 2.4 μM tubulin in the absence or in the presence of 3.3 μM noscapine in 10 mM sodium phosphate/0.1 mM GTP buffer (pH 7.00) at room temperature. (D) [3H]Colchicine binding competition with noscapine. (E) Noscapine promotes microtubule assembly in PEM/DMSO solution. (F) Noscapine inhibits microtubule assembly in PG/glycerol buffer. (G and H) Electron microscopy from control and noscapine-treated microtubules. (Bar = 0.15 μm.)
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