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By Karla Gale
NEW YORK Jul 22, 2003 (Reuters Health) - A new antiangiogenic agent derived from magnolia grandiflora seed cones, honokiol, prevents proliferation of endothelial cells and inhibits tumor growth in vivo.
Furthermore, honokiol is systemically available in an animal model and exhibits no toxicity, senior investigator Dr. Jack L. Arbiser and associates report in the Journal of Biochemistry for June 19.
A number of chemopreventive agents have been isolated from other plants, such as epicatechin gallate from tea and resveratrol from grapes, Dr. Arbiser of Emory University School of Medicine, Atlanta, told Reuters Health. Many do not exhibit any activity against established tumors in vivo, however. Another drug, curcumin, has some tumor activity when used topically but it is "poorly absorbed and rapidly excreted," he said, thus preventing its use as a systemic agent.
Dr. Arbiser and colleagues had previously developed a rapid bioassay that examines proliferation of the transformed endothelial cell line SVR. Two purified components of an aqueous extract of magnolia cones, magnolol and honokiol, both caused a dose-dependent decrease in SVR cell numbers, but honokiol was the more potent of the two.
After 18 hours, treatment with honokiol, but not magnolol, doubled the number of early apoptotic cells in SRV cell culture. By 48 hours, the number of early apoptotic cells had increased 7.7-fold, affecting 10.8% of the total cells. Honokiol exhibited preferential inhibition of endothelial cells over fibroblasts, confirming its classification as an angiogenesis inhibitor.
Honokiol blocks vascular endothelial cell growth factor receptor-2 (VEGFR2) autophosphorylation, the authors found, and this activity appears to be mediated by TNF-related apoptosis-inducing ligand (TRAIL).
The researchers also found that intraperitoneal honokiol inhibited tumor growth by about 50% in mice inoculated with angiosarcoma cells, without causing weight loss or other obvious toxicities.
Honokiol is used in traditional Asian medicines because it possesses anxiolytic properties, Dr. Arbiser noted, so purified preparations of the compound can be easily obtained. He does not rule out the possibility that other agents in magnolia tea could also have chemotherapeutic properties.
Another practical aspect of hokoniol is that it has not yet been patented, he added, making it a more promising investment for pharmaceutical companies.
"We are trying now to find the precise target of this drug," he said, "and we are developing synthetic derivatives so that we can easily produce large quantities that can be tested in mice and then in larger animals."
He cautioned, however, that no one should "go out and drink magnolia tea until we know more about its potential toxicities."
* Journal of Biochemistry 2003, June 19
Blood. 2005 Jul 15;106(2):690-7. Epub 2005 Mar 31. Related Articles, Links
The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells.
Battle TE, Arbiser J, Frank DA.
Department of Medical Oncology, Mayer 522B, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.
B-cell chronic lymphocytic leukemia (B-CLL) remains an incurable disease that requires innovative new approaches to improve therapeutic outcome. Honokiol is a natural product known to possess potent antineoplastic and antiangiogenic properties. We examined whether honokiol can overcome apoptotic resistance in primary tumor cells derived from B-CLL patients. Honokiol induced caspase-dependent cell death in all of the B-CLL cells examined and was more toxic toward B-CLL cells than to normal mononuclear cells, suggesting greater susceptibility of the malignant cells. Honokiol-induced apoptosis was characterized by the activation of caspase-3, -8, and -9 and cleavage of poly(adenosine diphosphate-ribose) polymerase (PARP). Exposure of B-CLL cells to honokiol resulted in up-regulation of Bcl2-associated protein (Bax) and down-regulation of the expression of the key survival protein myeloid-cell leukemia sequence 1 (Mcl-1), which is associated with response to treatment in B-CLL patients. In addition, B-CLL cells pretreated with interleukin-4 (IL-4), a cytokine known to support B-CLL survival, underwent apoptosis when subsequently incubated with honokiol, indicating that honokiol could also overcome the prosurvival effects of IL-4. Furthermore, honokiol enhanced cytotoxicity induced by fludarabine, cladribine, or chlorambucil. These data indicate that honokiol is a potent inducer of apoptosis in B-CLL cells and should be examined for further clinical application either as a single agent or in combination with other anticancer agents.
Arch Cardiol Mex. 2004 Apr-Jun;74(2):108-17. Related Articles, Links
[Study of Magnolia grandiflora extracts in guinea pigs cardiac muscle]
[Article in Spanish]
del Valle Mondragon L, Tenorio Lopez FA, Torres Narvaez JC, Zarco Olvera G, Pastelin Hernandez G.
Departamento de Farmacologia, Instituto Nacional de Cardiologia Ignacio Chavez, Tlalpan, Mexico, DF. firstname.lastname@example.org
Several extracts from diverse Magnolia grandiflora varieties were pharmacological evaluated in the cardiac muscle. From March to July, flowers and leaves from Magnolia grandiflora, native from the National Institute of Cardiology "Ignacio Chavez", from north, west, and orient zones from Mexico City, and from Puebla, Colima and Chiapas states were collected.They were separately processed and the extracts were obtained by maceration with ethanol-water (1:3 v/v) at 4 degrees C during two weeks. Qualitative analysis was accomplished with thin-layer, column and high-performance liquid chromatographies (HPLC). Functional and molecular analysis was made by specific chemical reactivity and by protonic magnetic resonance (RMN 1H). Pharmacological evaluation was completed in isolated and perfused male guinea pigs hearts. Extracts, fractions, and compounds were administrated by serial bolus in a gradual dose-response curves study in which left intraventricular pressure and coronary perfusion pressure were recorded, evaluating by such the positive inotropic and vasodilator effects of Magnolia grandiflora extracts. Vulgarenol and 2-p-hydroxyphenyl-2-hydroxy-ethylamine were isolated and identified, and the obtained results suggest that its positive inotropic and vasodilator effects are owed to these substances, being complemented by magnograndiolide and tyramine.
Br J Pharmacol. 2006 Mar 6; [Epub ahead of print] Related Articles, Links
Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells.
Chen SC, Chang YL, Wang DL, Cheng JJ.
1Institute of Clinical Medicine, National Yang-Ming University and Division of Cardiovascular Medicine, Taipei Medical University-Wan-Fang Hospital, Taipei, Taiwan.
Magnolol (Mag), an active constituent isolated from the Chinese herb Hou p'u (Magnolia officinalis) has long been used to suppress inflammatory processes. Chronic inflammation is well known to be involved in vascular injuries such as atherosclerosis in which interleukin (IL)-6 may participate. Signal transducer and activator of transcription protein 3 (STAT3), a transcription factor involved in inflammation and the cell cycle, is activated by IL-6. In this study, we evaluated whether Mag can serve as an anti-inflammatory agent during endothelial injuries. The effects of Mag on IL-6-induced STAT3 activation and downstream target gene induction in endothelial cells (ECs) were examined. Pretreatment of ECs with Mag dose dependently inhibited IL-6-induced Tyr705 and Ser727 phosphorylation in STAT3 without affecting the phosphorylation of JAK1, JAK2, and ERK1/2. Mag pretreatment of these ECs dose dependently suppressed IL-6-induced promoter activity of intracellular cell adhesion molecule (ICAM)-1 that contains functional IL-6 response elements (IREs). An electrophoretic mobility shift assay (EMSA) revealed that Mag treatment significantly reduced STAT3 binding to the IRE region. Consistently, Mag treatment markedly inhibited ICAM-1 expression on the endothelial surface. As a result, reduced monocyte adhesion to IL-6-activated ECs was observed. Furthermore, Mag suppressed IL-6-induced promoter activity of cyclin D1 and monocyte chemotactic protein (MCP)-1 for which STAT3 activation plays a role. In conclusion, our results indicate that Mag inhibits IL-6-induced STAT3 activation and subsequently results in the suppression of downstream target gene expression in ECs. These results provide a therapeutic basis for the development of Mag as an anti-inflammatory agent for vascular disorders including atherosclerosis
PHARMACOPOEIAL HISTORY.—The first (1820) pharmacopoeia failed to recognize any species of Magnolia. The 1830 revision (Philadelphia) gave place in the secondary list to three species, "Magnolia glauca, Magnolia acuminata and Magnolia tripetala; the officinal portion being "the bark." The New York edition of same date, (1830,) recognized the bark of Magnolia glauca, referring to it as "Bark of the Small Magnolia, or Sweet Bay." From 1830 to 1880 the three species of the Philadelphia edition remained officinal, occupying the secondary list until 1880, when the distinctions, primary and secondary were discarded.
The pharmacopoeia, excepting the New York edition, 1830, has it will be seen recognized three species, Magnolia glauca, Magnolia acuminata and Magnolia Umbrella (under the name tripetala). The reason for selecting these three is obviously because they are the most Northern species. In our opinion it would have been better to have specified the Magnolia glauca alone, as this shrub is the most aromatic, and presumably superior to others in medical action. Had it been the intention to mention the trees that supply the bark of commerce Magnolia glauca, Magnolia acuminata, Magnolia Umbrella, and Magnolia macrophylla should have been named.
None of the species of Magnolia are in use at present by the medical profession of America, and have not been employed for a generation. This assertion is based upon the reports of correspondents from every section, and from all the large cities of America, in accordance with which we accept that Magnolia should not be retained in the Pharmacopoeia.
CONSTITUENTS.—Dr. John Floyd, 1806, found by distillation with water, in the bark of Magnolia Umbrella and Magnolia acuminata, an aromatic oil in very small amount; and by extraction with alcohol, a resin and bitter principles. His chemical examination indicated that the resin wasthe characteristic constituent.
Coxe, 1825, states in his American Dispensatory, that the fresh bark of Magnolia glauca contains the aforenamed substances, and it is evident that his assertion is upon the authority of Dr. Floyd, although, credit is withheld. These statements were repeated by subsequent writers until 1842.
Dr. Stephen Proctor, 1842, made an analysis of the bark of Magnolia grandiflora, being led to do so by the botanical relationships between the genera Magnolia and Liriodendron. He sought to find the liriodendrin of Prof. Emmett, and by Emmett's process, employing magnolia bark instead of liriodendron, he obtained "numerous acicular crystals." He did not, however, assert that they were identical with liriodendrin, but that it "appears to be analogous to that of the liriodendrin." He also found a resinous body and a volatile oil.
Dr. W. H. Harrison, 1862, reports as the result of an analysis of the bark of Magnolia glauca, a resin and volatile oil; from the fruit he obtained much fixed oil and small amounts of fragile transparent crystals that appeared upon the filter paper, when the alcoholic solution of the resinous body obtained by Emmet's process for liriodendrin, was filtered. He states that "the crystals crack under the teeth and when freed from resinous matter have little taste or odor." This was his only description of them. It is evident that they were not the liriodendrin of Emmet, but a new body now known as magnolin.
Wallace Procter 1872, found that an alcoholic tincture of the fruit of Magnolia Umbrella, deposited transparent colorless crystals that were insoluble in cold water; slightly soluble in boiling water; very soluble in alcohol, ether, chloroform, carbon bisulphide and benzine; neutral to litmus paper and not basic. These crystals were obtained by other processes, one being to boil the tincture of the fruit with lime or magnesia, cool, filter, and add water to the filtrate. After some days crystals appeared, some half an inch in length. It seemed that the nearer the crystals were obtained in a state of purity, the less taste was apparent. In this connection, we will say that Prof. J. M. Maisch has supplied us with small specimens of these crystals of magnolin, now yellowish by age, but perfectly tasteless and colorless when recrystalised. Mr. Proctor also found a soft pungent resin, fixed oil, volatile oil, a hard resin but no liriodendrin.
It is therefore recorded that the different species of Magnolia contain in addition to the usual constituents of plants, a volatile oil, resinous matters, and a crystalline body, magnolin, that is not identical with liriodendrin, but no alkaloid has ever been isolated.
INDIAN PHARMACEUTICAL ASSOCIATION
2002 > MAY - JUNE
Indian Journal of Pharmaceutical Sciences
(Scientific Publication of the Indian Pharmaceutical Association)