Searching for Novel Cancer Chemopreventive Plants and Their Products: the Genus Zanthoxylum
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Current Drug Targets, 2011, 12, 1895-1902 1895 Searching for Novel Cancer Chemopreventive Plants and their Products: The Genus Zanthoxylum Francesco Epifano*,1, Massimo Curini2, Maria Carla Marcotullio2 and Salvatore Genovese1 1Dipartimento di Scienze del Farmaco, Università “G. D’Annunzio” di Chieti-Pescara, Via dei Vestini 31, 66013 Chieti Scalo (CH), Italy 2Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università degli Studi di Perugia, Via del Liceo, 06123 Perugia, Italy Abstract: The genus Zanthoxylum (Rutaceae) comprises about 250 species, of which many are used as food, often as condiments, substituting pepper due to the pungent taste of fruits, seeds, leaves, and bark, and therapeutic remedies especially in Eastern Asian countries and in Central America. The whole plant is also consumed as an ingredient of soups and salads. The aim of this review is to examine in detail from a phytochemical and pharmacological point of view what is reported in the current literature about the anti-cancer and chemopreventive properties of phytopreparations or individual active compounds obtained from edible plants belonging to this genus. Keywords: Anti-cancer activity, cancer chemoprevention, edible plants, prenyloxyphenylpropanoids, Rutaceae, Zanthoxylum. INTRODUCTION EDIBLE PLANTS OF THE GENUS ZANTHOXYLUM EXHIBITING ANTI-CANCER PROPERTIES Cancer is nowadays one of the major causes of death all over the world. Although many therapeutic remedies have Zanthoxylum ailanthoides Siebold & Zucc. been developed and used, most of which with appreciable Zanthoxylum ailanthoides, commonly known as success, prevention and cure of this severe syndrome is a “Japanese prickly-ash”, is a plant originary of the East-Asia, research field of current interest. In the last decade several growing most abundantly in the mountain regions of central reports indicated that different kinds of tumors could be prevented “simply” following a correct and suitable lifestyle and south Japan. Leaves are used as condiment, like cooked seeds, due to their pungent flavour and taste, that closely [1]. In this frame dietary factors seem to play a crucial role, resemble red pepper-based condiments. The resin contained especially in the prevention of cancers affecting the gastro- in the bark and roots is medically used as an anti-tussive, intestinal and respiratory apparatus, blood, kidney, and many carminative, and stimulant agent [3]. An active principle other organs and tissues [2]. Following this tendency from Z. ailanthoides, the neolignan ailanthoidol (AT) (1), numerous studies were carried out showing that dietary feeding with edible plants led to favorable epidemiological was seen to exert at different levels marked chemopreventive effects against tumor promotion [4]. outcomes in terms of tumor incidence and mortality. So the search for novel vegetables and fruits as dietary feeding cancer chemopreventive remedies is a field of current and HO growing interest. OH The genus Zanthoxylum (Rutaceae) comprises about 250 O species, small trees and shrubs, all native to warm temperate OCH OCH3 and subtropical areas worldwide. Many species are used as 3 food and therapeutic remedies especially in Eastern Asian 1 countries and in Central America, often as condiments, substituting pepper-based ones due to the pungent taste of In their study Tseng and coworkers first assessed the fruits, seeds, leaves, and bark. Moreover the whole plant is radical quenching properties of compound (1). At a con- also consumed as an ingredient of soups and salads. Being centration of 0.05 mM, AT scavenged 64% of DPPH free several species of the genus Zanthoxylum employed as food radicals. Basing on these preliminary results, they tested the in many parts of the world, the aim of this review has been to anti-oxidant properties of (1) in an in vivo system. The examine in detail the anti-tumor properties of such plants in Authors employed the ICR mouse as a model to investigate view of their potential use as alimentary cancer preventive the effect of AT on 12-O-tetradecanoyl-phorbol-13-acetate- remedies. (TPA)-induced H2O2 production in skin. Pre-treatment with AT at three dosage levels (0.5, 1.0, and 2.5 mM) signifi- cantly diminished the TPA (5nM)-mediated production of *Address correspondence to this author at the Dipartimento di Scienze del H2O2 by 83%, 90%, and 96% respectively. It’s noteworthy Farmaco, Università “G. D’Annunzio” di Chieti-Pescara, Via dei Vestini 31, that animals treated only with TPA (5 nM) recorded a 3-fold 66013 Chieti Scalo (CH), Italy; Tel: +3908713554654; Fax: increase in H2O2 concentration compared to untreated con- +3908713554912; E-mail: [email protected] trols. As myeloperoxidase (MPO) levels are used as a marker 1873-5592/11 $58.00+.00 © 2011 Bentham Science Publishers 1896 Current Drug Targets, 2011, Vol. 12, No. 13 Epifano et al. for the quantification of reactive oxygen species (ROS)- of tambulin was seen to be effective in ameliorating the producing leukocyte infiltration into the derms [5], Tseng tumor mass in solid tumors harbouring animals, and and coworkers also measured the extent of TPA-induced- significantly increased the life spam in ascites tumor MPO activation and the effect of AT. While the individual harbouring animals (89.5 %). It’s also noteworthy that the response to TPA led to a 28-fold increase in MPO activity simultaneous i.p. administration of tambulin (20 mg/kg) compared to controls, the application of the same dosages potentiated the effects of known chemotherapeutics like seen above of (1) inhibited significantly (58%, 61%, and cyclophosphamide and γ-radiation treatment leading to a 97% respectively) the MPO activation. Being well known substantial decrease of the volume of solid tumors in mice. that inflammatory processes are closely linked to tumor pro- motion and development, in another series of experiments, Zanthoxylum americanum Mill. Tseng and coworkers determined the inhibitory effects of AT on TPA-induced ear oedema in mice, as well as the exp- Zanthoxylum americanum, commonly known as ression and activation of inflammation marker enzymes like “northern prickly ash”, is a plant native to North America, cycloxygenase-2 (COX-2) and ornithine decarboxylase ranging from Quebec region (where it’s also known as (OD). The topical application of 20 µL of AT 2.5 mM prior “Clavalier”) to Georgia and Oklahoma. It has been used for a to TPA (5nM) was seen to inhibit the formation of oedema very long time as a medicinal plant for the relief of toothache by nearly 96%. It’s also important to put in evidence that AT and several other complaints [9, 10]. Still and coworkers alone did not provoke any oedema formation. The topical isolated from this plant four pyranocoumarins, namely application of AT was also accompanied by the inhibition of dipetalyne (3), alloxanthoxyletin (4), xanthoxyletin (5), and induction of epidermal hyperplasia and inflammatory cells xanthyletin (6), and two lignans, sesamin (7) and asarine (8). infiltration. The effect of AT on COX-2 and OD consisted also in a significant dose-dependent decrease of the expres- sion and/or activity of these two latter enzymes. Finally O R Tseng and coworkers assessed the effect of AT in the pro- motion of mouse skin carcinogenesis induced by benzo[a] pyrene (B[a]P) and TPA. Pre-treatment with AT topically administered in the range of concentrations 0.5 – 2.5 mM, H3CO O O O O O led to a 25% - 50% decrease in papillomas formation, as well R as in their multiplicity: in fact the average number of papillo- 5 R = OCH3 mas/mouse was 4.9 in animals treated only with B[a]P and 3 R = isopentenyl 4 R = H 6 R = H TPA, while decreased to 1.9, 1.9, and 0.8 in animals pre- treated with AT at the dosages of 0.5, 1.0, and 2.5 mM O respectively. O O O O Zanthoxylum alatum Roxb. O H H Zanthoxylum alatum, commonly known as “winged pric- H H O kly ash”, is a plant growing in East Asia, particularly wide- O O O spread in forests and hot valleys to 1800 meters in the 8 Himalayas. Seeds, ground into a fine powder, are used as a O 7 O condiment in substitution of pepper. Roasted seeds are also an ingredient of the Chinese dish called “five spice mixture” [6]. Moreover seeds are medically used by local populations All these secondary metabolites were able to inhibit the as a tonic in the treatment of fevers, dyspepsia, and cholera incorporation of tritiated thymidine into HL-60 (human [7]. Fruits, branches, and thorns are considered to be carmi- leukemia) cells, being the IC50 values 2.18 µM for dipetaline, native and stomachic and are often used as a remedy for 5.08 µM for alloxanthoxyletin, 15.28 µM for xanthoxyletin, toothache. Tambulin (3,5-dihydroxy-7,8,4’-trimethoxyfla- 14.91 µM for xanthyletin, 7.66 µM for sesamin, and finally vone) (2), a flavone extracted from this plant, was seen to 11.64 µM for asarin [9]. exert a mild in vitro anti-cancer activity [8]. Zanthoxylum chalibeum O Zanthoxylum chalibeum is commonly medically used in OH the East African countries, especially Rwanda and Tanzania as an anti-plasmodial agent [11, 12]. The dichloromethane and methanol extracts from the leaves of this plant exhibited H3CO O a mild cytotoxic activities in vitro against HL-60 cells (IC50 OCH3 30.16 and 137.31 µg/mL respectively). OCH3 2 Zanthoxylum fagara (L.) Sarg. Zanthoxylum fagara, commonly known as “limoncillo” The recorded IC50 values were 33.0 µM in L929 (murine in Central America, is a plant growing in Florida, Caribbean aneuploid fibrosarcoma), 42.0 µM in HT-29 (human colon Islands, northern Mexico, Colombia, and Brazil. Decoction adenocarcinoma), and 45.1 µM in K562 (human erythro- of its bark is used as a diaphoretic and stimulant agent and to myeloblastoid leukemia) cells.