Journal of Ethnopharmacology 119 (2008) 195213

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Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Review

Ficus spp. (g): Ethnobotany and potential as anticancer and anti-inammatory agents
Ephraim Philip Lansky a, , Helena M. Paavilainen a , Alison D. Pawlus b , Robert A. Newman a,b
a b

Punisyn Pharmaceuticals, POB 9945, Haifa, Israel Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA

a r t i c l e

i n f o

a b s t r a c t
This review explores medieval, ancient and modern sources for ethnopharmacological uses of Ficus (g) species, specically for employment against malignant disease and inammation. The close connection between inammatory/infectious and cancerous diseases is apparent both from the medieval/ancient merging of these concepts and the modern pharmacological recognition of the initiating and promoting importance of inammation for cancer growth. Also considered are chemical groups and compounds underlying the anticancer and anti-inammatory actions, the relationship of g wasps and g botany, extraction and storage of g latex, and traditional methods of preparing g medicaments including g lye, g wine and medicinal poultices. 2008 Published by Elsevier Ireland Ltd.

Article history: Received 29 November 2007 Received in revised form 4 June 2008 Accepted 8 June 2008 Available online 28 June 2008 Keywords: Anticancer Anti-inammatory Cancer Ficus Figs Inammation

Contents 1. 2. 3. 4. 5. 6. 7. 8. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Botany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ethnomedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological activities of Ficus spp. and their isolated constituents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 196 199 206 209 209 209 209 210 210

1. Introduction The use of foods and medicinal plants to improve health is nearly as old as humanity. Among such, none may be older than the g, which recent investigations have indicated has been cultivated for over 11,000 years, possibly predating cereal grains (Kislev et al., 2006). Though this nding has recently been challenged (Lev-Yadun et al., 2006), it has also been supported (Gibbons, 2006). A num-

Corresponding author at: Horev Medical Center, POB 9945, Haifa, Israel. Tel.: +972 545 273 156; fax: +972 48 305324. E-mail address: punisyn@gmail.com (E.P. Lansky). 0378-8741/$ see front matter 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.jep.2008.06.025

ber of Ficus species are used as food and for medicinal properties in Ayurvedic and Traditional Chinese Medicine (TCM) especially amongst people where these species grow. These uses, however, originated and are most widely found in the Middle East. It is reasonable to consider that a survey of ethnomedical uses of a plant may provide useful clues for drug discovery. Two primary criteria are typically considered in such ethnomedical research to identify a clear preferential use of a particular plant or for a specic disease or symptom. These are: (1) frequency of citation of the association between plant and disease by particular authors and (2) consistency of use of the particular plant for a given disease over time. Once a plant is deemed strongly associated with use for a particular illness, including reports of amelioration of symptoms

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of the disease or syndrome following use of the specic herb, proof of concept studies could seek conrmation of the traditional presumed pharmacological action(s), focusing and economizing drug discovery (Paavilainen, 2005). The present review juxtaposes ancient and medieval medical references to gs and their various parts with relevant modern studies of their pharmacology, emphasizing potential anticancer activities. We have also included references to the treatment of inammatory diseases, since inammation is known to play a role in the etiology of certain cancers (Lansky and Newman, 2007). In

assessing this literature, an attempt has been made to be as specic as possible, nonetheless, some overlap and fuzziness in diagnostic categories is inevitable. Bold Arabic numerals in the text refer to chemical structures given in Fig. 1. 2. Botany Ficus, the g genus, consists of over 800 species and is one of about 40 genera of the mulberry family, Moraceae (Woodland, 1997). The Ficus genus should not be confused with the cus species,

Fig. 1. Structures of compounds previously identied from Ficus spp.

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Fig. 1. (Continued )

the prickly pear cactus Opuntia cus-indica (L.) Mill (Linars et al., 2007; Ncibi et al., 2008; Zourgui et al., 2008). The g species of greatest commercial importance, Ficus carica L. (the common g), consists of numerous varieties with signicant genetic diversity (Salhi-Hannachi et al., 2006). Other notable species of Ficus are Ficus religiosa L. (the Bo tree which sheltered the Buddha as he divined the Truths), Ficus elastica Roxb. ex Hornem. (the rubber tree), Ficus benghalensis L. (the banyan tree) and Ficus racemosa L. (syn. glomer-

ata, the giant cluster tree) (see Fig. 2). Many of these species possess auxiliary aerial root systems extending to the ground from their branches or trunks. All Ficus spp. possess latex-like material within their vasculatures, affording protection and self-healing from physical assaults. Within the general category of fruits, gs are examples of syconia, multiple fruits with a distinctive inside-out structure. These comprise collections of druplets and are eshy hollow receptacles,

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Fig. 1. (Continued )

each with a small opening at the apex, called an ostiole. Tiny owers are massed on the inside walls and are not visible externally. Because of this, Chinese medicine refers to gs as the no ower fruit (Li, 1578). The skin of the fruit is thin and tender when fresh and the eshy wall is whitish, pale yellow, pink, rose, red, or purple, depending on the species. The g is juicy and sweet when ripe, gummy with latex before ripening. Seeds vary greatly in size and number from 30 to 1600 per fruit and the leaves are described as hand-shaped (Li, 1578). Each Ficus species depends upon an intricate symbiosis with a specic species of g wasp that lays its eggs within the gs, and usually, only within a single Ficus species, itself dependent

on that single wasp for pollination. For Ficus carica, for example, the dedicated pollinating wasp species is Blastophaga psenes (L.) Grav. The female pollinating wasp enters the g through the ostiole, or through exit holes in the g wall, prepared for the female by the male of its species, who dies soon after performing this function (Haine et al., 2007; Marussich and Machado, 2007; Proft et al., 2007). The female pollinator wasp may seek out more than one receptive g tree, recognizing a trees availability by specic volatile compounds (Grison-Pige et al., 2002). In addition to the symbiotic wasp species, there are also parasitic species that enter the g by following the tracks of the female pollinator wasps.

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Fig. 1. (Continued )

3. Ethnomedicine Our review of the medicinal uses of gs for potential cancer and diseases with cancer-related etiologies includes ancient, medieval and early modern herbals from the Middle East and Europe. These texts cover the period from the 1st century CE to the 17th century, and geographically cover the area from Persia to Spain and from North Africa to England and Germany, with

an additional text from Mexico. This review also contains Mexican plant lore understood according to the European paradigms (Lpez, 1982). These herbals were based on ancient Greek authors, especially Dioscorides (4090) and Galen (2nd century), whose texts were translated rst to Arabic and then to Latin, often through Hebrew. During the process of translation and dissemination, new plants and new medicinal uses were added based on the local plant lore and the physicians own experiences

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Fig. 1. (Continued ).

(Levey and Al-Khaledy, 1967; Lieber, 1981; Dols, 1984; Riddle, 1985). Identication of a particular Ficus species from these old works has been done on the basis of earlier research into plant nomenclature (Dioscorides, 1902, 1933; Yule, 1903; Fischer, 1929; Andr, 1956; Schmucker, 1969; Stannard, 1979; Glare, 1982; Hunt, 1989; Daems, 1993; Lev, 2002). Parts of the earlier Greek and Arabic texts include descriptions of the tree and later European texts have detailed drawings which aid in their identication (Fuchs, 1549; Gerard, 1633; Parkinson, 1640). Most concern Ficus carica and Ficus sycomorus, though close relatives of these may have been included under the common names g and sycomore (Riddle, 1992). While the common name sycamore is used to refer to plants such as the American Sycamore (Platanus occidentalis L.) the Californian or Western Sycamore (Platanus racemosa Nutt.) or the European maple (Acer pseudoplatanus L.), the sycamore of the Bible refers to Ficus sycomorus. The parts of Ficus carica and Ficus sycomorus used for treatment of tumors and diseases associated or characterized by inammation include the fruits in different stages of ripening, fresh or dry, tree bark, leaves, twigs and young shoots, and also latex from the bark, fruit and young branches. Additionally, ashes of the g tree and g stalks and lye made of the ashes of the branches and wood were used, as well as wine made from the fruits, as summarized in Table 1. (Note: The authors referred to in Table 1 are treated in a separate list after the regular reference section. In many cases the actual year of the publication of the historical work is not known, so known years of the authors life, year of death, or century, have been included.) Table 2 provides clarication of the sources indicated in Table 1. The preparation of the different g tree products (Table 1) varied in complexity from a mere splitting of a pulpy g for use as a poultice to preparing lye from the ashes of the different parts of the plant. Additionally, the fruit and latex were often combined with other botanical and mineral ingredients. The fruit was usually dried for storage purposes and occasionally boiled and its stage of ripeness and freshness often specied. Usually, g tree products for cancer and other tumors and swellings were used externally, even when the tumor or swelling was internal, such as intestinal ailments, and often combined with other ingredients such as blue

ag (Iris versicolor L.), barley and fenugreek. Both latex and fruits were, however, also employed orally (Table 1). Pertinent to Table 1, erysipelas is used to indicate any of a variety of streptococcal skin infections. Infection of a hair follicle is indicated by furuncle, while an abscess, with its walled-off collection of purulent matter, by impostume. A general term for skin diseases with itching and eruptions, and which might encompass eczema, psoriasis and cutaneous herpes infections, is tetters. Several terms for therapeutic mineral compounds are employed, including green vitriol for ferrous sulfate, natron for a hydrated form of sodium carbonate, quicklime for calcium oxide, and vitriol for sulfuric acid or any of its metal salts, such as ferrous, copper or zinc. Corrosive or necrotizing effects in general are indicated by phagedenic (American Heritage Dictionary, 2006; Merck, 2006; Dorland, 2007). Greek transliterations, such as karkinos, lead to karkinoma, an eating sore or ulcer, karkinosis, formation of cancerous growth, or simply, karkinodes, cancerous. The Latin, gangraena gives gangrene, but also implies cancerous, phagedenic (eating), ulcer, carcinoma, a malignant tumor, and cancer, a non-healing malignant ulcer (Lewis and Short, 1879; Liddell, 1940). Arabic gives waram or awram for swelling or tumor; the Latin apostema, designating abscess, is a medieval translation of waram. Any of waram, apostema, tumor, and even lump, and the Spanish hinchazn can suggest a cancerous excrescence or protuberance. Hard tumors are indicated by the Arabic waram salib, salabah or jasha for hardening, or their Medieval Latin translation, apostema dura or scirros (Ibn Sina, 1877, 1505; Lewis and Short, 1879; Lane, 18631893; Gruner, 1930), hardness by the Latin duritia or Spanish dureza. Hot tumors connote inammation (which may also encompass malignant processes) and are denoted by the Greek phlegmone, an inamed tumor or boil, while the more general concept of ulcer (i.e., a break in the skin or a mucous membrane caused by the loss of the epidermis and at least part of the dermis) is indicated by the Greek helkoma, the Latin ulceratio, ulcus and ulceris, or the Arabic qarh and quruh. Spreading and/or corroding wounds, ulcers or sores are designated by the Greek nomas, the Latin nome or the Arabic quruh sayah and obstinate or malignant ulcers by the Greek kakoethes, the Latin cacoethes or the

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Fig. 2. Ficus species in Haifa, Israel in early September. (a) Ficus microcarpa with aerial roots hanging from branch and wrapping around the trunk; (b) a small, organically grown g from Ficus carica cut latitudinally exposing the seeds and vestigial owers; (c) foliage from Ficus elastica; (d) close-up of two immature gs and a healthy leaf from a Ficus carica on a residential street. (All photos by Zipora Lansky.)

Arabic quruh habithah. Chronic disease in general underlies the Greek chronios, the Latin veter and the Arabic muzammin (Lane, 18631893; Lewis and Short, 1879; Liddell, 1940; Whitaker, 1993; Merck, 2006). The common g fruit of Ficus carica is readily recognized by the Greek sykon (Dioscorides, 1902; Fischer, 1929) or syke agria (Dioscorides, 1933), the latter also referring to wild g (Dioscorides, 1902). The Ficus carica tree may be indicated by syke or sykea though these designations may also refer to the gwort family, Scrophulariaceae. Also, Ficus carica is indicated by the Arabic tin (Schmucker, 1969; Lev, 2002), the Latin carice, dried gs (Albertus Magnus, 1867; Andr, 1956; Stannard, 1979), or cus (Andr, 1956; Glare, 1982; Daems, 1993) or Ficus sylvestris (Stannard, 1979), the latter also for wild g, the German Feige,

pl. Feigen (Fuchs, 1549; Gerard, 1633; Parkinson, 1640), and the English g or gge (Gerard, 1633; Parkinson, 1640; Hunt, 1989). The Greek sykomoron refers to Ficus sycomorus (Dioscorides, 1902; Fischer, 1929; Lev, 2002) as does the Latin Ficus pharaonis (Gerard, 1633; Fischer, 1929) and the English sycomore (Gerard, 1633; Parkinson, 1640). The Arabic tin barri denotes either Ficus carica or Ficus sycomorus (Lev, 2002) as does the Latin Ficus fatus (Fischer, 1929; Stannard, 1979). The English arched Indian g tree is Ficus benghalensis (Yule, 1903), the Arabic jamiz could be either Ficus benghalensis (Glare, 1982) or Ficus sycomorus (Lev, 2002). Generically, the Spanish higuera refers to any Ficus species while the Greek olynthos denotes winter gs (Dioscorides, 1902) or unripe gs (Dioscorides, 1933), referring to the stage of a certain g stage of growth.

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Table 1 Ancient and medieval medicaments for cancer and inammation derived from Ficus spp. Ficus species carica, sycomorus Medicament Fresh or dried fruit Indications Cancer, carcinoma, ulcers, hot swellings, hard tumors, throat swelling, skin ulcers, dermatitis, burning chest inammation (s); chronic disease (improves color) Tumors, swellings, furuncles, paronychia (s) Hard tumors, swellings, dermatitis, erysipelas, carbuncles Splenomegaly Tumors of trachea and lung; chronic disease Swelling of tonsils, trachea; hard tumors, splenomegaly; chronic cough Chronic cough, lung problems/pains, chest diseases, pulmonary TB Bubonic swellings in groin and axillae, pustules Malignant, exuding ulcers, especially of leg or groin Tumors/swellings of jaw and soft esh, tumor emollient, furuncles Tumors, swellings; hard tumors, cutaneous ulcers Tumors, swellings; hard tumors, cutaneous ulcers Swelling of tonsils, trachea Swellings of throat Hard tumors (to ripen and dissolve); hepatomegaly, splenomegaly Hard tumor, splenomegaly, hepatomegaly Hard tumor, splenomegaly, hepatomegaly Chronic diarrhea Paronychia Groin bubos (to ripen and break) Malignant ulcers, thigh ulcers, foul running ulcers Ulcers, plague ulcers Leg ulcers Malignant leg ulcers Hot tumors Moist head ulcers Ulcers with honey-like exudates Head ulcers Moist head ulcers Ulcers with honey-like exudates Pustules on head Gout Tetter, dermatitis, tumors, cancer, Tumors Running ulcers Moist ulcers with honey-like exudates Route of administration Poultice, eating References Al-Antaki (s), Albertus Magnus (c,s), Bock (c), Dioscorides (c), Fuchs (c), Ibn Butlan (s), Ibn Sina (c,s), Parkinson (s), Plinius (c), Tabernaemontanus (s) Al-Razi (s), Ibn Sina (s), Ishaq Israeli (c) Albertus Magnus (s), Ibn Sina (s) Ibn Sina Ibn Sina Al-Razi (s), Dioscorides (c), Ibn Al-Baytar (c), Ishaq Israeli (c), Runus (c), Al-Razi, Bock, Dioscorides, Fuchs, Gerard, Ishaq Israeli, Plinius, Runus Dioscorides, Ibn Al-Baytar, Ibn Sina Al-Razi, Bock, Dioscorides, Fuchs, Ibn Al-Baytar, Parkinson, Plinius, Tabernaemontanus Fuchs Bock, Ishaq Israeli, Ibn Al-Baytar, Parkinson Ibn Al-Baytar Runus Ibn Sina Al-Antaki, Al-Razi, Fuchs, Dioscorides, Galenus, Ibn Al-Baytar, Ibn Sina Al-Razi Lopez Al-Antaki Bock, Ibn Sina, Plinius Gerard Bock, Parkinson, Tabernaemontanus Bock, Parkinson Plinius Fuchs Plinius Ibn Al-Baytar; Al-Razi Ibn Al-Baytar; Al-Razi Ibn Sina Al-Razi Ishaq Israeli Ishaq Israeli Fuchs, Gerard Fuchs, Gerard, Ibn Sina, Plinius Gerard Bock, Tabernaemontanus Dioscorides, Ibn Sina

carica, sycomorus carica, sycomorus sycomorus carica carica, sycomorus carica carica carica carica carica carica carica carica carica

Fresh or dried fruit mashed with wax Fresh/dried fruit in barley our Fresh/dried fruit, gum ammoniac Fig fruit-wine Dried or fresh fruit aqueous decoction Dried fruit aqueous decoction with hyssop Dried fruit aqueous decoction with blue ag, natrona and quicklime (CaO) Fresh/dried fruit, vitriol (FeSO4 or CuSO4 ) Dried g decocted in wine Dried g, boiled or chopped, ground and/or mashed with fenugreek and barley seeds Dried gs soaked in red vinegar nine days Dried g decocted in honeyed wine Dried g, pomegranate peel aqueous decoction Dried fruit aqueous decoction, barley our, +/wheat/fenugreek our Dried fruit decoction (or chopped), barley our, thyme, hot pepper, ginger, mint or hyssop Dried fruit aqueous decoction (or chopped), cabbage or blue ag Chopped dried fruit and leaf, sugar Fresh/dried fruit, pomegranate peels (pounded or decocted) Fresh/dried fruit, lily roots, wheat our, fenugreek our, linseed, marshmallow root Fresh/dried fruit, copper vitriol (CuSO4 ) Fresh/dried fruit, sourdough, salt Pulpiest fresh/dried fruit, verdigris Dried fruit, shoemakers blackening Unripe fruit Unripe fruit, vinegar, salt Unripe fruit, honey Unripe fruit, powdered Unripe fruit, vinegar, milk Fresh fruit, honey Fresh ripe fruit, natron, vinegar Fresh/dried fruit, vinegar, fenugreek our Leaf Leaf, marshmallow root Leaf, vinegar, salt (pounded) Leaf, honey

Ointment Poultice Poultice Drink Gargle; in poultice or ointment; drink Drink Poultice Poultice Ointment or poultice Poultice, simultaneously eating pickled gs (Ibn Al-Baytar) Four gs eaten per day concurrent with poultice Gargle Gargle Poultice/ointment, food +/ rarefying/dissolving medicines Food Poultice Eaten Poultice, ointment Poultice Poultice Poultice Poultice Poultice Fumigation Poultice Poultice Poultice Poultice Poultice Poultice Poultice Rubbed externally, poultice Poultice Poultice Poultice

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carica carica sycomorus carica carica carica carica carica carica carica carica carica carica carica carica carica carica carica carica carica carica

carica carica, sycomorus

Leaf, wine Milk (latex), especially from tree bark in beginning of spring Boiled milk (latex) and fruit Boiled milk (latex) with almond (or starch) Milk (latex), barley our (or barley mush or wheat our or corn our) Milk (latex), egg yolk Milk (latex), egg yolk, dried milk Milk (latex), starch Milk (latex), fenugreek our (+/vinegar) Lye made from ashes of wood, or water in which ashes repeatedly dipped Lye made from ashes of wood, FeSO4 Water repeatedly contacted with lye of wood ashes, pomegranate peels Ashes from wood Ashes of wood, olive oil (or honey) Ashes of wood, vinegar, salt (pounded) Ashes of stalks springing from roots burned twice, white lead Bark of tree, oil Young white shoots Twigs, honey Sawdust-like scrapings from barked branches

sycomorus carica carica carica carica carica carica carica, sycomorus

Phagadenic ulcers Tumors, hard tumors (to dissolve or cause to burst), spleen/liver hardness, splenomegaly, head ulcers Hard tumors (to disperse) Hard tumors, ulcers, tumors of uterus Running head ulcers, spreading sores, tetter Ulcers (to open) Ulcers (to open) Ulcers (to open) Gout Cancer, spreading cankers, moist ulcers, malignant, deep, foul, gangrenous ulcers, gastric ulcers, chronic diarrhea Malignant leg ulcers Paronychia Gastric ulcers (c), deep putrid ulcers, spreading ulcers (s), erysipelas (s), chronic diarrhea (c) Skin ulcers (to clean) Ulcers of head Eye ulcers Gastric ulcers Furuncles Ulcers with honey-like exudates Impetigo

Poultice Poultice/ointment, drink (often together) Poultice Drink Poultice Poultice Liniment Drink Poultice, ointment Poultice, ointment, on sponge, drink, enema Poultice Poultice Enema (c), skin application (s), External application External application Ophthalmic Drink Ointment External application External application

Plinius Al-Antaki (s), Al-Razi (s), Bock (c), Dioscorides (s), Gerard (s), Ibn Al-Baytar (s), Ibn Sina (s), Parkinson (s), Tabernaemontanus (s) Al-Razi Al-Razi, Ibn Al-Baytar Al-Razi, Bock, Dioscorides, Fuchs, Gerard, Lopez, Parkinson, Tabernaemontanus Fuchs Plinius Ulcers (to open) Al-Razi, Dioscorides, Fuchs, Ibn Al-Baytar, Lopez, Plinius Al-Razi (c), Bock (c), Dioscorides (c), Ibn Sina (c), Parkinson (c), Tabernaemontanus (c,s) Ibn Sina Ibn Sina E.P. Lansky et al. / Journal of Ethnopharmacology 119 (2008) 195213 Al-Antaki (s), Al-Razi (c), Al-Antaki Al-Razi Fuchs, Plinius Fuchs, Plinius Fuchs, Plinius Dioscorides, Fuchs, Plinius Plinius

carica carica carica, sycomorus carica sycomorus carica carica carica carica carica

carica or c = Ficus carica L., sycomorus or s = Ficus sycomorus L. a Mineral of hydrated sodium carbonate Na2 CO3 10H2 O.

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Table 2 The herbals and medical encyclopedias referred to in Table 1 Author/title Plinius Dioscorides Galen Al-Tabari Ishaq Israeli Al-Razi Ibn Sina Ibn Butlan Albertus Magnus Ibn Al-Baytar Runus de Rizardo Hieronymus Bock Leonhart Fuchs Jacob Theodor Tabernaemontanus Gregorio Lpez Al-Antaki John Gerard John Parkinson Title The Natural History The Materials of Medicine Complete Works The Paradise of Wisdom Complete Works The Comprehensive Book on Medicine The Canon of Medicine Tables of Health Book on Growing Things Comprehensive Book of Simple Drugs and Foods Herbal Herbal on the Differences, Names and Properties of Herbs Notable Commentaries on the History of Plants New Complete Herbal Treasure of Medicines Memorandum Book for Hearts and Comprehensive Book of Wonderful Marvels Herball The Botanical Theater Date 2379 c. 4090 2nd cent. 800875 855955 c. 865925 9801037 d. 1066 12061280 d. 1248 13th cent. 14981554 15011566 15221590 15421596 d. 1599 15451611/1612 15671650 Authors location Italy Anazarbos (Turkey) Pergamum/Rome Persia Kairouan Persia Persia Baghdad/Cairo/Antioch Germany Spain/Egypt/Syria Italy Germany Germany Germany Mexico Syria/Cairo England England Language Latin Greek, translated into German Greek + Latin Arabic Arabic, translated into Latin Arabic Arabic Arabic, translated into Latin Latin Arabic Latin German Latin German Spanish Arabic English English

Table 3 Notes on the collection and preparation of ancient and medieval Ficus medicaments Preparation Latex Ficus carica L. Flows from young leaves when broken (Bock, 1964); fruit and leaves of cultivated trees yield Euphorbia-like white latex if broken before fruits are ripe (Gerard, 1633) Juice taken from branches of the wild g tree when sapful, before buds appear by pounding and pressing. Juice is dried in the shade and stored (Dioscorides, 1902; Plinius (19671970) Made of ashes of burnt branches of wild and cultivated g trees. Ashes must be steeped in water long and often. Used by moistening a sponge in it often and applying it immediately (Dioscorides, 1902) Dried gs placed with water in vessel closed with linen for 10 days. Water can be replaced with same amount of juice from pressing fresh gs or grapes, which improves the wine. Can be repeated every 10 days up to ve times, the last time used for vinegar. Can add salt or seawater to prevent spoilage. May also place thyme and fennel on bottom of vessel, then gs, then thyme and fennel, until full (Dioscorides, 1902) Ficus sycomorus L.

Latex storage

The latex taken from tree at the beginning of spring before it brings forth fruit, by breaking the outside of the bark with a stone (if it is broken deeper, no latex comes out). The drops are gathered in a sponge or wool, dried, formed (into pills), and stored in earthenware jars (Dioscorides, 1902)

Lye

Wine

Same as for Ficus carica L. (Dioscorides, 1902)

Antiquarian texts also provide potentially practical insight into how these parts were processed for medical applications. A survey of the most common of these is presented in Table 3. Ayurvedic medicine utilizes at least three different Ficus spp., as summarized in Table 4 (Kapoor, 1990; Khan and Balick, 2001). Figs are used as external treatments for eczema, leprosy, rheumatism, sores, ulcers and pains. Like TCM (see below), Ayurvedic medicine

recommends gargling with g decoctions for sore throats and the ingestion of gs as a treatment for diarrhea. Other Ayurvedic uses include treatment of dysentery, gonorrhea and menorrhagia and as an aphrodisiac (Kapoor, 1990). In TCM, the g is only rarely used, partly because this fruit is found only in the most southern regions of China, but also because the fruits are regarded more as a food rather than a medicine, and

Table 4 Uses of Ficus spp. in Ayurvedic medicine (according to Kapoor, 1990) Ficus species benghalensis benghalensis benghalensis. racemosa racemosa racemosa racemosa racemosa racemosa religiosa racemosa racemosa racemosa Plant material Infusion of leaves and buds Latex, seeds, fruits Infusion of bark Fruits Fruits, boiled and strained Ground leaves mixed with honey Latex (milky juice) Bark powder Roots Bark water decoction or infusion Latex boiled with milk Oil infused with root bark Fruits Use Diarrhea and dysentery External treatment for pains, bruises, rheumatism, lumbago, sores, ulcers To lower blood sugar in diabetes, to treat dysentery, gonorrhea, and as a powerful tonic in seminal weakness Aphthae, menorrhagia, hemoptysis Gargle for sore throat Bilious affections Diarrhea, hemorrhoids Diabetes Dysentery Cooling, gonorrhea, ulcers, skin diseases, scabies, hiccup, vomiting Aphrodisiac External treatment for excema, leprosy, rheumatism Laxative, digestive

benghalensis = Ficus benghalensis L., racemosa = Ficus racemosa L., religiosa = Ficus religiosa L.

E.P. Lansky et al. / Journal of Ethnopharmacology 119 (2008) 195213 Table 5 Contemporary ethnomedical uses of Ficus spp. suggestive of anti-neoplastic and anti-inammatory actions Use Place Ficus species benghalensis carica carica carica carica carica carica carica carica carica pachyrrachis salicifolia Unspecied Unspecied aurantiacea carica carica carica carica carica carica carica carica carica carica carica glomerata insipida, maxima maxima maxima maxima obtusifolia padifolia pungens racemosa racemosa racemosa reexa religiosa religiosa religiosa salicifolia scabra septica septica septica Plant part Latex Fruit Dried fruit Fresh latex Latex Fresh fruit, sap Fresh fruit Latex Latex from stem Fresh latex Entire plant Latex Bark References Reddy et al. (1989) Takeuchi et al. (1978) Siddiqui and Husain (1994) Zagari (1992)

205

(A) Modern ethnomedical uses of Ficus spp. against neoplasia Warts, external India Cancer Japan Tumor (mixed with Tamarix dioica and acetic acid) India Warts, mixed with egg yolk or vegetable oil to Iran wounds and ulcers Warts, aqueous decoction, external Italy Warts, external France Cancer, oral USA Warts, verrucas Italy Warts, external Turkey Warts, external Tunisia Breast tumors Tonga Warts, external Oman Cancer, external Thailand Tumors Guinea (B) Modern ethnomedical uses of Ficus spp. against inammation Pruritis Malaysia Mastitis Turkey Bronchitis, pleurisy, cystitis, nephritis (oral) Iran External applications of decoction for inammations Iran Adenitis Peru Pain, scorpion bite, external Turkey Boils and eruptions, external India Dermatitis, external Oman Pharyngitis, stomatitis, oral Canary Islands Bee sting, external Turkey Excema, hemorrhoids, oral Turkey Head wounds, external Turkey Ophthalmia, external India Rheumatism, external Peru Rheumatism, oral, infusion Brazil Gingivitis, decoction, oral Honduras Gingivitis, decoction, oral Honduras Toothache, headache, traumatic injury, decoction, Mexico oral Traumatic injury, decoction, oral Mexico Body pains, heated leaves applied externally Papua New Guinea Gripping gastralgia, decoction, oral India Pneumonia, oral India Stomachic, oral India Gout, gastrointestinal ulcers, infusion, oral Rodrigues Islands Tuberculosis, fever, paralysis, oral, hemorrhoids, Bangladesh rectal Unconsciousness Fiji Asthma, cardiac edema. Gastritis, decoction, oral South Korea Bruised nger or toes, external (in a formula) Oman Ophthalmia, infusion, external Rotuma (Fiji) Headache, gastroenteritis, leaf buds, oral Papua New Guinea Gastralgia, seawater infusion, oral Buka Island Cephalgia, somatic pains, heated, moistened leaves Papua New Guinea with salt as a hot compress to forehead and other areas, crushed directly to a sores, covered by a similar leaf, external Dermatitis, external Papua New Guinea For lumbago, four to six leaves with pinch of potash Nigeria ground together and applied to affected part after making nine incisions; for dislocated limbs, leaves burned in hot ash to decolorize, then rubbed on affected parts Lumbago, rheumatism, decoction, oral Japan Toothache, direct to cavity Indonesia Gastroenteritis, oral Indonesia Wounds from poisoned arrows, decoction, external India Vulnerary after childbirth, menstrual pains, Madagascar, Sierra Leone decoction, oral Asthma, powdered, 23 g in warm water infusion, India oral Toothache, direct Mexico Toothache, direct Upper Amazon Basin Headaches, leaves tied onto ears Papua New Guinea

Lokar and Poldini (1988) Novaretti and Lemordant (1990) Liebstein (1927) De Feo et al. (1992) Yesilada et al. (1995) Boukef et al. (1982) Holdsworth (1974) Ghazanfar and Al-Sabahi (1993) Wang (1973) Vasileva (1969) Ahmad and Holdsworth (1994) Sezik et al. (1997) Zagari (1992) Zagari (1992) Ramirez et al. (1988) Fujita et al. (1995) Sebastian and Bhandari (1984) Ghazanfar and Al-Sabahi (1993) Darias et al. (1986) Yazicioglu and Tuzlaci (1996) Yazicioglu and Tuzlaci (1996) Yazicioglu and Tuzlaci (1996) Singh et al. (1996) Duke and Vasquez (1994) Diaz et al. (1997) Lentz et al. (1998) Lentz (1993) Dominguez and Alcorn (1985) Dominguez and Alcorn (1985) Nyman et al. (1998) Sharma et al. (1992) Sebastian and Bhandari (1984) Mukherjee and Namhata (1990) Gurib-Fakim et al. (1996) Khanom et al. (2000) Singh (1986) Han et al. (1984) Ghazanfar and Al-Sabahi (1993) McClatchey (1996) Holdsworth et al. (1989) Holdsworth (1980) Holdsworth (1992)

Leaf Fruit Fruit Dried leaf Dried fruit Latex from stem Fresh latex Leaf Dried shoots Fresh latex Dried leaf Ash from stem + twigs Latex Latex Dried leaf Dried leaf + stem Sap, wood Fresh latex Fresh bark and/or root Leaf Fruit Fresh leaf juice Root juice, sap Bark + leaf Dried fruit Dried leaf juice Unspecied Leaf Fresh bark Dried buds Fresh leaf Fresh leaf

subcuneata thonningii

Fresh latex Fresh leaf

Holdsworth and Sakulas (1986) Bhat et al. (1990)

thunbergii toxicaria toxicaria Unspecied Unspecied Unspecied Unspecied Unspecied Unspecied

Fresh leaf Fresh latex Leaf Dried bark Dried bark Dried fruit Latex Latex Leaf

Kitajima et al. (1994) Mahyar et al. (1991) Grosvenor et al. (1995) Bisset and Mazars (1984) Quansah (1988) Nisteswar and Kumar (1980) Zamora-Martinez and Pola (1992) Lewis and Elvin-Lewis (1984) Holdsworth (1989)

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served after being salted like pickles, cooked in water or sun-dried. Medicinally, gs are recommended both for improving the appetite and as treatment for diarrhea. The juice of cooked gs is used as a gargle for sore throats; while for hemorrhoids, a decoction of the leaves is applied locally while simultaneously, cooked gs are also ingested orally. Chinese medicine considers the leaves to be slightly poisonous (Li, 1578). We have endeavored to have a look at contemporary ethnopharmacological uses of Ficus species against cancer and inammation, summarized in Table 5. In Table 5A, references to cancer specically, in addition to benign neoplasias, such as warts, are included. Table 5B provides examples of ethnomedical scenarios where inammation is likely involved, and where the action of the drug may have an anti-inammatory effect. Some medical uses with potential anti-inammatory components, however, such as diabetes mellitus and fever in general, were not included in the table. Other scenarios such as pain in general, toothache, and even unconsciousness were included. Antibiotic uses of the plants were also generally excluded, though an example for pneumonia was included for the probability of an anti-inammatory component of the drugs action. Similarly, actions against gingivitis and pharyngitis which were included may involve both antibiotic and anti-inammatory components. Overall, this summary reveals potential anti-inammatory actions at multiple control points, some accumulated experience with use of g components against cancer, and many examples of the action of the latex on warts. 4. Biological activities of Ficus spp. and their isolated constituents Initial scientic investigations of g latex against cancer were performed in the 1940s (Ullman et al., 1945, 1952; Ullman, 1952). Injection of an extract of Ficus carica latex was found to inhibit growth of a benz-[a]-pyrene-induced sarcoma and resulted in the disappearance of small tumors in albino rats. This work inspired the isolation and structure elucidation of a mixture of 6-O-acyl- d-glucosyl- -sitosterol isoforms from the latex of Ficus carica that demonstrated anti-proliferative activity in several tumor cell lines (Rubnov et al., 2001). Whether this sitosterol alone accounts for the anti-tumor activity in mice originally observed by Ullman et al. is, at present, unclear. Since Ullmans initial research, a number of Ficus spp. and their constituents have been evaluated for biological activities relevant to cancer and inammation, including; Ficus awkeotsang Makino,
Table 6 Anti-neoplastic, anti-inammatory and antioxidant actions of Ficus components Plant part Jelly in fruit Bark (aqueous) Bark Leaf Fruit Latex Latex Root bark (aqueous) Leaf Aerial roots Bark (ethanolic) Bark Not specied Ficus species awkeostang benghalensis benghalensis carica carica carica carica elastica exasperata microcarpa racemosa racemosa racemosa Leucopelargon in derivative Phenolics Mixed beta-sitosterols Flavonoid pigment Relevant chemistry Cationic peptides

Ficus benghalensis, Ficus carica, Ficus elastica Roxb. ex Hornem., Ficus exasperata Vahl, Ficus microcarpa L. f., and Ficus racemosa. Table 5 summarizes these results, which include some promising anticancer activities. For example, a supercritical uid extraction of a g residue demonstrated moderate anti-proliferative activity in U937, 95D, and AGS cancer cells in vitro and inhibited the growth of hepatic carcinoma xenografts by approximately 49% in mice (Wang and Ma, 2005). An extract of Ficus citrifolia Mill. enhanced intracellular accumulation of daunomycin in K562/R7 leukemic cells and the cytotoxic effect of vinblastine on the growth of MESSA/Dx5 cells. Both of these cell lines overexpress P-glycoprotein, which plays a role in multi-drug resistance. These results suggest a possible adjunct role in cancer chemotherapy by inhibition of multi-drug resistance (Simon et al., 2001). A non-cytotoxic compound, racemosic acid (64), from the bark of Ficus racemosa, potently inhibited COX-1 and 5-LOX activity in vitro at IC50 values of 90 and 18 M, respectively (Li et al., 2004). The avonoids apigenin (38), carpachromene (40), and norartocarpetin (56), from the stems of Ficus formosana Maxim, were cytotoxic in several cancer cell lines (Sheu et al., 2005). Also, lectins, chemical complexes of polysaccharides and/or metalloproteins, found in g seeds (Ray et al., 1993), have been found to cause agglutination of white blood cells from patients with leukemias, but not of the white cells from healthy persons (Agrawal and Agarwal, 1990). Some of the most promising cytotoxic compounds in Ficus species include a series of triterpenoids with C-28 carboxylic acid functional groups and phenanthroindolizidine alkaloids. Thus, triterpenoids (101, 102, 104, 116, 125, and 126), isolated from the aerial roots of Ficus microcarpa demonstrated cytotoxicity in three human cancer cell lines with IC50 values from 4.0 to 9.4 M, including HONE-1 nasopharyngeal carcinoma cells, KB oral epidermoid carcinoma cells, and HT29 colorectal carcinoma cells (Chiang et al., 2005). The phenanthroindolizidine alkaloids, including a number of antone and tylophorine derivatives, also show promise as cytotoxic agents. Their activity, which occurs in the low nanomolar range, has been demonstrated in vitro by multiple researchers working with the National Cancer Institutes tumor cell line panel (Strk et al., 2000; Gao et al., 2004; Damu et al., 2005; Fu et al., 2007). For example, the alkaloids, cuseptine-A (6), (+)-tylophorine (19), and a mixture of (+)-antone (1) and (+)isotylocrebrine (12) from the leaves of Ficus septica Burm. f., and O-methyltylophorinidine (15) from the twigs and stems of Ficus hispida exhibited potent cytotoxic activity in several cancer cell lines with IC50 values around 2 M (Peraza-Sanchez et al., 2002; Wu et al., 2002).

Pharmacological action Cell cycle arrest and apoptosis, inhibition of proliferation in leukemia cells Antioxidant, decrease increase in antioxidant enzymes Antioxidant in rat Antioxidant in diabetic rat Inhibits LDL oxidation in humans Resolution of papillomatosis on bovine teat Inhibition of proliferation of several cancer cell lines Inhibits carrageenan-induced ear edema and adjuvant-induced arthritis in rat Antioxidant, preservation of palm oils Cytotoxic against several cell lines Inhibits COX-1 Antioxidant, inhibits COX-1, 5-LOX Prevents renal carcinogenesis and oxidation

Reference Chang et al. (2005) Shukla et al. (2004) Augusti et al. (2005) Perez et al. (2003) Vinson et al. (2005) Hemmatzadeh et al. (2003) Rubnov et al. (2001) Sackeyo and Lugeleka (1986) Umerie et al. (2004) Chiang et al. (2005) Li et al. (2003) Li et al. (2004) Khan and Sultana (2005)

Triterpenes Racemosic acid

Authorities: Ficus awkeostang Makino, Ficus benghalensis L., Ficus elastica Roxb. ex Hornem., Ficus exasperata Vahl.

E.P. Lansky et al. / Journal of Ethnopharmacology 119 (2008) 195213 Table 7 Compounds identied in Ficus spp. Compound name Leaves Antone (1) 10S,13aR-antone N-oxide (2) Dehydrotylophorine (3) 2-Demethoxytylophorine (4) 4,6-Bis-(4-methoxyphenyl)-1,2,3-trihydroindolizidinium chloride (5) Ficuseptine A (6) 14 -Hydroxyisotylocrebrine N-oxide (11) Tylophorine (19) Bergapten (26) 4 ,5 -Dihydropsoralen (27) 5,6-O- -d-diglucopyranosylangelicin (28) Esculin (29) 5-O- -d-glucopyranosyl-6-hydroxyangelicin (30) 6-O- -d-glucopyranosyl-5-hydroxyangelicin (31) 5-O- -d-glucopyranosyl-8-hydroxypsoralen (32) 8-O- -d-glucopyranosyl-5-hydroxypsoralen (33) Marmesin (34) Umbelliferone (36) Genistin (47) Isoquercitrin (52) Kaempferitrin (53) Rutin (58) 5-Acetyl-2-hydroxyphenyl- -d-glucopyranoside (60) Vanillic acid (75) Uracil (76) Baurenol (103) Ficusogenin (structure not given) Lupeol (112) 24-Methylenecycloartanol (113) -Sitosterol- -d-glucoside (119) Squalene (122) -Taraxasterol ester (124) 3,4,5-Trihydroxydehydro- -ionol-9-O- -d-glucopyranoside (127) Leaves and stems Isotylocrebrine (12) Tylocrebrine (16) Leaves and roots Psoralen (35) -Sitosterol (118) Stigmasterol (121) Stems Ficuseptine B (7) Ficuseptine C (8) Ficuseptine D (9) Hispidine (10) 10S,13aR-isotylocrebrine N-oxide (13) 10S,13aS-isotylocrebrine N-oxide (14) 6-O-methyltylophorinidine (15) 10R,13aR-tylocrebrine N-oxide (17) 10S,13aR-tylocrebrine N-oxide (18) 10R,13aR-tylophorine N-oxide (20) 10S,13aR-tylophorine N-oxide (21) Carpachromene (40) Isoglabranin (50) Norartocarpanone (55) Norartocarpetin (56) Ficuformodiol A (66) Ficuformodiol B (67) (R)-()-Mellein (70) 3-(7-Methoxy-2,2-dimethyl-2H-6-chromenyl)-(E)-propenoic acid (71) Obovatin (72) Spatheliachromene (74) Ficus spp. septica septica septica hispida septica septica septica septica carica carica rucaulis septica rucaulis rucaulis rucaulis rucaulis carica carica septica rucaulis septica carica, rucaulis septica septica septica carica carica carica carica septica septica carica rucaulis septica septica hirta, carica carica, septica hirta, septica septica septica septica hispida septica septica hispida septica septica septica septica formosana formosana formosana formosana formosana formosana formosana formosana formosana formosana Class Alkaloid Alkaloid Alkaloid References

207

Alkaloid Alkaloid Alkaloid Alkaloid Coumarin Coumarin Coumarin Coumarin Coumarin Coumarin Coumarin Coumarin Coumarin Coumarin Flavonoid Flavonoid Flavonoid Flavonoid Phenolic, other Phenolic, other Pyrimidine Sterol Triterpenoid Sterol Sterol Sterol Triterpenoid Sterol Other Alkaloid Alkaloid Coumarin Sterol Sterol Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Alkaloid Flavonoid Flavonoid Flavonoid Flavonoid Phenolic, other Phenolic, other Phenolic, other Phenolic, other Phenolic, other Phenolic, other

Baumgartner et al. (1990) and Wu et al. (2002) Damu et al. (2005) Yang et al. (2006) Venkatachalam and Mulchandani (1982) Baumgartner et al. (1990) Wu et al. (2002) and Yang et al. (2006) Wu et al. (2002) Wu et al. (2002) and Yang et al. (2006) Damjanic and Aka ic (1974) and c Innocenti et al. (1982) Innocenti et al. (1982) Chang et al. (2005) Wu et al. (2002) Chang et al. (2005) Chang et al. (2005) Chang et al. (2005) Chang et al. (2005) Innocenti et al. (1982) Innocenti et al. (1982) and Wu et al. (2002) Wu et al. (2002) Chang et al. (2005) Wu et al. (2002) el-Kholy and Shaban (1966) and Chang et al. (2005) Wu et al. (2002) Wu et al. (2002) Wu et al. (2002) Ahmed et al. (1988) el-Kholy and Shaban (1966) Saeed and Sabir (2002) Ahmed et al. (1988) Wu et al. (2002) Wu et al. (2002) el-Kholy and Shaban (1966) Chang et al. (2005) Wu et al. (2002) and Damu et al. (2005) Wu et al. (2002) and Damu et al. (2005) Damjanic and Aka ic (1974), Innocenti c et al. (1982) and Li et al. (2006) el-Kholy and Shaban (1966), Wu et al. (2002) and Li et al. (2006) Wu et al. (2002) and Li et al. (2006) Damu et al. (2005) Damu et al. (2005) Damu et al. (2005) Venkatachalam and Mulchandani (1982) Damu et al. (2005) Damu et al. (2005) Venkatachalam and Mulchandani (1982) Damu et al. (2005) Damu et al. (2005) Damu et al. (2005) Damu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005) Sheu et al. (2005)

208 Table 7 (Continued ) Compound name Stems and roots Apigenin (38)

E.P. Lansky et al. / Journal of Ethnopharmacology 119 (2008) 195213

Ficus spp. hirta, formosana nymphaeifolia nymphaeifolia nymphaeifolia nymphaeifolia nymphaeifolia nymphaeifolia nymphaeifolia nymphaeifolia nymphaeifolia hirta hirta hirta beecheyana beecheyana. beecheyana. beecheyana. beecheyana. beecheyana. hirta. hirta. hirta microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpa microcarpaf. microcarpa microcarpa microcarpa microcarpaf. microcarpaf. benghalensis benghalensis microcarpaf. microcarpaf. racemosa racemosa carica carica

Class Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Flavonoid Phenolic, other Phenolic, other Phenolic, other Phenolic, other Phenolic, other Phenolic, other Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Triterpenoid Anthocyanin Anthocyanin Flavonoid Flavonoid Phenolic, other Phenolic, other Anthocyanin Anthocyanin

References Sheu et al. (2005) and Li et al. (2006) Darbour et al. (2007) Darbour et al. (2007) Darbour et al. (2007) Darbour et al. (2007) Darbour et al. (2007) Darbour et al. (2007) Darbour et al. (2007) Darbour et al. (2007) Darbour et al. (2007) Li et al. (2006) Li et al. (2006) Li et al. (2006) Lee et al. (2002) Lee et al. (2002) Lee et al. (2002) Lee et al. (2002) Lee et al. (2002) Lee et al. (2002) Li et al. (2006) Li et al. (2006) Li et al. (2006) Chiang et al. (2005) Chiang and Kuo (2001) Chiang and Kuo (2001) Chiang et al. (2005) Chiang et al. (2005) Chiang and Kuo (2000) Chiang et al. (2005) Chiang and Kuo (2000) Chiang and Kuo (2001) Chiang and Kuo (2001) Chiang and Kuo (2001) Chiang and Kuo (2000) Chiang and Kuo (2002) Chiang et al. (2005) Chiang and Kuo (2001) Chiang et al. (2005) Chiang and Kuo (2000) Chiang and Kuo (2000) Chiang and Kuo (2002) Chiang and Kuo (2001) Chiang et al. (2005) Chiang and Kuo (2000) Chiang et al. (2005) Chiang et al. (2005) Chiang et al. (2005) Chiang and Kuo (2002) Chiang et al. (2005) Chiang and Kuo (2002) Chiang and Kuo (2002) Chiang and Kuo (2002) Chiang et al. (2005) Chiang et al. (2005) Chiang and Kuo (2000) Chiang et al. (2005) Chiang et al. (2005) Daniel et al. (2003) Daniel et al. (2003) Li and Kuo (1997) Li and Kuo (1997) Li et al. (2004) Li et al. (2004) Solomon et al. (2006) Solomon et al. (2006)

Stem bark Alpinumisoavone (37) Cajanin (39) Derrone (41) 5,7-Dihydroxy-4-methoxy-3 -(2,3-dihydroxy-3-methylbutyl)isoavone (42) Erycibenin A (43) Erythrinin C (44) Genistein (46) 3 -(3-Methylbut-2-enyl)biochanin A (54) 5,7,2 -Trihydroxy-4 -methoxyisoavone (59) Roots Hesperidin (48) 5-Hydroxy-4 ,6,7,8-tetramethoxyavone (49) 4 ,5,6,7,8-Pentamethoxyavone (57) trans-4,5-Bis(4-hydroxy-3-methoxyphenyl)-1,3-dioxacyclohexane (62) erythro-2,3-Bis(4-hydroxy-3-methoxyphenyl)-3-ethoxypropan-1-ol (63) threo-2,3-Bis(4-hydroxy-3-methoxyphenyl)-3-ethoxypropan-1-ol (64) 2,3-Dihydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone (65) threo-3-(4-Hydroxy-3,5-dimethoxyphenyl)-3-ethoxypropane-1,2-diol (68) 3-Hydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-1-propanone (69) 3 -Acetoxy- -amyrin (77) 3 -Acetoxy- -amyrin (78) 3 -Hydroxy-stigmast-5-en-7-one (108) Aerial roots 3 -Acetoxy-12,19-dioxo-13(18)-oleanene (79) 3 -Acetoxy-1 ,11 -epidioxy-12-ursene (80) 3 -Acetoxy-12 ,13 -epoxy-11 -hydroperoxyursane (81) 3 -Acetoxy-11 ,12 -epoxy-16-oxo-14-taraxerene (82) 3 -Acetoxy-11 ,12 -epoxy-14-taraxerene (83) 3 -Acetoxy-20 ,21 -epoxytaraxastane (84) 3 -Acetoxy-21 ,22 -epoxytaraxastan-20 -ol (85) 3 -Acetoxy-20 ,21 -epoxytaraxastan-22 -ol (76) 3 -Acetoxy-11 -hydroperoxy-13 h-ursan-12-one (87) (20S)-3 -acetoxy-20-hydroperoxy-30-norlupane (88) 3 -Acetoxy-18 -hydroperoxy-12-oleanen-11-one (89) 3 -Acetoxy-19 -hydroperoxy-20-taraxastene (90) 3 -Acetoxy-11 -hydroxy-11-(12 13)abeooleanan-12-al (91) 3 -Acetoxy-25-hydroxylanosta-8,23-diene (92) (20S)-3 -Acetoxylupan-29-oic acid (93) 3 -Acetoxy-25-methoxylanosta-8,23-diene (94) 3 -Acetoxy-19 -methoxy-20-taraxastene (95) 3 -Acetoxy-22 -methoxy-20-taraxastene (96) 3 -Acetoxyolean-12-en-11 -ol (97) 3 -Acetoxy-12-oleanen-11-one (98) 3 -Acetoxy-19(29)-taraxasten-20 -ol (99) 3 -Acetoxy-20-taraxasten-22 -ol(100) Acetylbetulinic acid (101) Acetylursolic acid (102) Betulonic acid (104) 29,30-Dinor-3 -acetoxy-18,19-dioxo-18,19-secolupane (105) 3,22-Dioxo-20-taraxastene (106) 3 -Hydroxy-20-oxo-29(20 19)abeolupane (107) Lupenol (110) Lupenol acetate (111) Oleanonic acid (114) 3-Oxofriedelan-28-oic acid (116) 20-Taraxastene-3 ,22 -diol (123) Ursolic acid (125) Ursonic acid (126) Bark 5,3 -Dimethyl leucocyanidin-3-O- -galactosyl cellobioside (24) 5,6-Dimethyl ether of leucopelargonidin-3-O- -l-rhamnoside (25) Ficuisoavone (45) Isolupinisoavone E (51) Bergenin (61) Racemosic acid (73) Fruits Cyanidin-3-O-glucoside (22) Cyanidin-3-O-rhamnoglucoside (23)

E.P. Lansky et al. / Journal of Ethnopharmacology 119 (2008) 195213 Table 7 (Continued ) Compound name Seeds Ficus benghalensis agglutinin (FBA) Latex 6-O-linoleyl- -d-glucosyl- -sitosterol (109) 6-O-oleyl- -d-glucosyl- -sitosterol (115) 6-O-palmitoyl- -d-glucosyl- -sitosterol (117) 6-O-stearyl- -d-glucosyl- -sitosterol (120) Ficus spp. benghalensis carica carica carica carica Class Lectin Latex Latex Latex Latex References Singha et al. (2007) Rubnov et al. (2001) Rubnov et al. (2001) Rubnov et al. (2001) Rubnov et al. (2001)

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Numbers in parentheses refer to structures in Fig. 1. Authorities: Ficus beecheyana Hook. & Arn.; Ficus benghalensis L.; Ficus carica L.; Ficus formosana Maxim.; Ficus hirta Vahl.; Ficus hispida L. f.; Ficus microcarpa L. f.; Ficus nymphaeifolia Mill.; Ficus racemosa L.; Ficus rucaulis Merr.; Ficus septica Burm. f.

Two antone derivatives have demonstrated potent activity in both a drug-sensitive KB-3-1 and a multi-drug resistant KB-V1 cell lines (Strk et al., 2000). Synthesis of these alkaloids and additional analogues has been undertaken for further biological investigations. Mechanistic studies of some tylophorine analogs demonstrated signicant inhibition of activator protein-1 (AP1), cyclic AMP response elements and nuclear factor- B (NF- B). Xenograft studies in nude mice found that a tylophorine analogue increased albumin expression and decreased -fetoprotein expression in HepG2 cells. This analogue did not, however, cause DNA breaks or apoptosis, suggesting it may exert its effect by inducing cancer cell differentiation (Gao et al., 2004). In a test of anti-inammatory activity, an aqueous extract of root bark obtained from Ficus elastica Roxb. ex Hornem signicantly reduced carrageenan-induced ear edema, comparable to the positive control, indomethacin, and also adjuvant-induced arthritis in rats (Sackeyo and Lugeleka, 1986). Extracts of the bark from Ficus racemosa inhibited COX-1 (Li et al., 2003) and 5-LOX enzymatic activities (Li et al., 2004) at 90 and 18 M as previously noted, and prevented chemically induced renal oxidation and carcinogenesis (Khan and Sultana, 2005). Furthermore, extracts of the leaves of Ficus racemosa demonstrated anti-inammatory activity against carrageenan, serotonin, histamine, and dextrane-induced rat paw edema models, similar to the positive control, phenylbutazone (Mandal et al., 2000). Also of interest is the therapeutic effect of g latex on bovine teat papillomatosis. Papillomas are typically benign tumors and spontaneously regress, though some undergo malignant transformation to squamous-cell carcinomas. Salicylic acid and Ficus carica latex were equally effective in treating teat papillomatosis in cows, suggesting that the anti-inammatory activity may be sufcient to reduce this common bovine disease (Hemmatzadeh et al., 2003). Figs also have been shown to possess antioxidant, hypolipidemic, and hypoglycemic activities. In a study using rabbits on high cholesterol diets, an aqueous extract of the bark of Ficus benghalensis signicantly reduced cholesterol and triglyceride levels compared with those fed the same high cholesterol diet alone. In addition to this hypolipidemic activity, there was a decrease in lipid peroxidation and an increase in antioxidant enzymes in rabbits given the g extract (Shukla et al., 2004). Ficus-derived antioxidant activity has also been cited as a reason for its effectiveness in alleviating symptoms of streptozotocin-mediated diabetes in rats (Perez et al., 2003). The leaves also protect against the formation of excessive peroxide levels in palm oil when used during its preparation, presumably due to the its antioxidant properties (Umerie et al., 2004). A gel-forming, pectin-like polysaccharide from the seeds of Ficus awkeotsang Makino has potential use in controlled-release drug delivery tablets (Miyazaki et al., 2004). 5. Clinical studies The majority of the medicinal uses of gs in humans are based on historical reports or anecdotal evidence with only a

few reports coming from modern clinical trials. In one such report, 40 g/day of dried gs were fed to healthy volunteers and found to potently reduce oxidation of low density lipoprotein (LDL) as measured by the trolox equivalent antioxidant capacity (TEAC) antioxidant assay (Vinson et al., 2005). In a second study, an aqueous decoction of Ficus carica leaves was effective in ameliorating post-prandial hyperglycemia in Type 1 diabetes mellitus and was well tolerated (Serraclara et al., 1998). Most recently, Ficus carica leaf latex proved as effective as cryotherapy when applied externally to common warts (Bohlooli et al., 2007). 6. Phytochemistry Phytochemical investigations on a number of Ficus species including Ficus benghalensis, Ficus carica, Ficus hirta Vahl, Ficus hispida L. f., Ficus microcarpa, Ficus nymphaeifolia Mill., Ficus rucaulis Merr., and Ficus septica Burm. f., were undertaken and led to identication of over 100 compounds, summarized in Table 6 and Fig. 1. A substantial number of these compounds are phenanthroindolizidine alkaloids from the leaves and stems of Ficus hispida and Ficus septica. Several coumarins were isolated from several different Ficus spp. and multiple avonoids have been identied from Ficus spp. stems, leaves, and roots. Also prominent were triterpenoids from the roots, leaves (Ahmed et al., 1988; Teixeira et al., 2006) and the latex (Chiang and Kuo, 2000; Chiang and Kuo, 2001; Rubnov et al., 2001; Chiang and Kuo, 2002; Saeed and Sabir, 2002; Chiang et al., 2005; Li et al., 2006). Additionally, 54 different triacylgylcerols were identied in Ficus carica seed oil using mass spectrometry (Holcapek et al., 2005). In another study, to determine the mechanism for attracting particular g wasps, an analysis of the volatile compounds of 20 Ficus species was instituted. Signicant variation was found in both the exact volatile compounds and their relative concentrations amongst the 20 species tested. These compounds were primarily simple terpenoids and other small aliphatics (Grison-Pige et al., 2002) (Table 7). 7. Toxicology As one of the oldest known human foods, gs as a fruit have a very high safety prole. However, the toxicological evaluation of other g products is in an early stage. Skin contact with latex may provoke allergic reactions like dermatitis, asthma and anaphylaxis (Chelminska, 2004) while orally administered latex may induce hallucinosis (Luna, 1984a,b). Effects other than discussed above may be therapeutic or toxic, depending on the clinical context (Ayinde et al., 2007). 8. Conclusions Fig trees of several different species show multiple cancer preventive, cancer therapeutic and anti-inammatory activities from

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their bark, roots, leaves, fruits and latex. Evidence of such uses originated in ancient and medieval times, with classical writers of those periods claiming the efcacious use of these parts in carcinomas, inammatory swellings, hard swellings, and tumors in general. Although these historical records are frequently difcult to translate into modern diagnostic categories, both the frequency of these citations, and in some cases, their specicity, provides condence that medicines deriving from Ficus trees were well-known for treating both cancers and inammatory processes, and that in many cases, amelioration of these conditions was subsequently observed. Pharmacological and chemical studies have demonstrated anti-neoplastic or anti-inammatory activity of both the crude extract and pure compounds. Of particular promise, due to their potent cytotoxic activity against a number of cancer cell lines, are the phenanthroindolizidine alkaloids and the triterpenoids with a C-18 carboxylic acid functional groups. In fact, these alkaloids, which have also been found in a small number of other plant genera, are currently under active investigation as potential therapeutic leads (Gao et al., 2004). In addition to these cytotoxic compounds, several avonoids, including anthocyanins, as well as other phenolic compounds, demonstrated antioxidant and anti-inammatory activities (Li et al., 2007). Furthermore, lectins in the seeds may function as immune modulators (Rabinovich et al., 2007; Singha et al., 2007). The sterols found in gs may also help bolster immunity, as well as inhibiting inammation and invasion while promoting apoptosis and differentiation (Bradford and Awad, 2007). Coumarins, in many cases, are selectively cytotoxic to cancer cells, and also have antioxidant activity and may interfere with formation of the lipoxygenase product 5-HETE to suppress inammation (Kulkarni et al., 2006). Some correlation between the ethnomedical employment and the pharmacological activities has been duly observed and noted in the present review. As only a small fraction of the known Ficus spp. and parts has been evaluated for anticancer and anti-inammatory activities, gs may constitute a rather large untapped source for new chemical entities with anticancer actions. Finally, in addition to the pharmacological potential for cancer treatment, rich opportunities for Ficus spp., especially from the fresh and dried fruits of Ficus carica, exist within the arena for functional foods and beverages (Vinson, 1999; Vinson et al., 2005). These opportunities derive primarily from the extremely benign safety prole of g fruit products, pleasant taste and its antioxidant constituents. Because the antioxidant action is also a means of lowering chronic anti-inammatory action and insulin resistance, g fruits hold potential in functional food approaches aimed at normalizing metabolic syndrome and boosting wellness beyond the widely accepted role of gs in the diet for improving bowel performance, and as a source of naturally sweet, readily available, quick energy.

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