http://informahealthcare.com/phbISSN 1388-0209 print/ISSN 1744-5116 online

Editor-in-Chief: John M. PezzutoPharm Biol, Early Online: 1–12

! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/13880209.2013.871641

REVIEW ARTICLE

Estonian folk traditional experiences on natural anticancer remedies:From past to the future

Katrin Sak1, Kadi Jurisoo2, and Ain Raal2

1NGO Praeventio, Tartu, Estonia and 2Department of Pharmacy, University of Tartu, Tartu, Estonia

Abstract

Context: Despite diagnostic and therapeutic advancements, the burden of cancer is stillincreasing worldwide. Toxicity of current chemotherapeutics to normal cells and theirresistance to tumor cells highlights the urgent need for new drugs with minimal adverse sideeffects. The use of natural anticancer agents has entered into the area of cancer research andincreased efforts are being made to isolate bioactive products from medicinal plants.Objective: To lead the search for plants with potential cytotoxic activity, ethnopharmacologicalknowledge can give a great contribution. Therefore, the attention of this review is devotedto the natural remedies traditionally used for the cancer treatment by Estonian people overa period of almost 150 years.Methods: Two massive databases, the first one stored in the Estonian Folklore Archives and thesecond one in the electronic database HERBA (http://herba.folklore.ee/), containing altogethermore than 30 000 ethnomedicinal texts were systematically reviewed to compile data about theEstonian folk traditional experiences on natural anticancer remedies.Results and conclusion: As a result, 44 different plants with potential anticancer properties wereelicited, 5 of which [Angelica sylvestris L. (Apiaceae), Anthemis tinctoria L. (Asteraceae), Pinussylvestris L. (Pinaceae), Sorbus aucuparia L. (Rosaceae), and Prunus padus L. (Rosaceae)] have notbeen previously described with respect to their tumoricidal activities in the scientific literature,suggesting thus the potential herbal materials for further investigations of natural anticancercompounds.

Keywords

Cancer treatment, ethnomedicine, naturalanticancer drugs

History

Received 29 September 2013Revised 15 November 2013Accepted 30 November 2013Published online 6 February 2014

Introduction

Nature has long been an important source of remedial agents

and the use of plants as medicine is as old as the human

civilization (Nahata et al., 2013; Stankovic et al., 2012).

An impressive number of modern drugs are isolated from

natural sources, based on their use in traditional medicine

(Stankovic et al., 2012).

Over the last decades, cancer is the most challenging

disease to cure and the second leading cause of death

worldwide (Paul et al., 2013; Susanti et al., 2012). Despite

the diagnostic and therapeutic advancements burden of this

devastating disease is continuously growing and according

to the estimation of the World Health Organization, the

approximate 12.7 million new cancer cases that occurred

globally in 2008 will be increased to 21.3 million by 2030

(Kim et al., 2011; Song et al., 2013). Numerous cytotoxic

drugs can destroy tumor and arrest disease progression but

most of them are too toxic to normal cells causing critical

critical to healthy tissues (Chung et al., 2010; Fan et al., 2012;

Susanti et al., 2012; Tripathy & Pradhan, 2013). This limits

their effectiveness and use as chemotherapeutic drugs and

highlights an urgent need to develop agents with minimal side

effects to normal organs. In order to address this need, the use

of natural phytochemicals has entered into the domain of

cancer research and increased efforts are being made to isolate

bioactive products from medicinal plants (Fan et al., 2012;

Jimenez-Medina et al., 2006; Paul et al., 2013; Rajkumar

et al., 2009). A wide variety of secondary metabolites

obtained from plants have been tested for their ability to

treat cancer (Rajkumar et al., 2009) and among at least

250 000 existing plant species more than one thousand are

found to possess significant anticancer properties (Aljuraisy

et al., 2012). Application of plant materials and extracts as

alternative cancer therapies has generally low toxicity and low

cost, another requirement for the development of new plant-

derived antitumor agents is ample supply in terms of plant

availability and yield of the chemotherapeutic compound

(Alshatwi et al., 2011; Schempp et al., 2002).

The search for anticancer agents from natural sources has

been successful worldwide. Active constituents are isolated

and are in the use of treatment of human tumors (Galvez

et al., 2003). Thus, about 60% of anticancer drugs

employed in cancer chemotherapy are derived from plant

sources; for example, taxol from Taxus brevifolia Nutt.

(Taxaceae), camptothecin from Captotheca acuminataCorrespondence: Katrin Sak, NGO Praeventio, Naituse 22-3, Tartu50407, Estonia. Tel: +372 53 341 381. E-mail: katrin.sak.001@mail.ee

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Decne. (Nyssaceae), etoposide from Podophyllum species,

vincristine from Catharanthus roseus (L.) G.Don

(Apocynaceae), and several others (Ghavami et al., 2010;

Nahata et al., 2013).

However, the management of cancer is still not up to the

mark and there are always needs to search new drugs for more

effective treatments. In this context, plants hold a certain

hope for the development of new therapies and studies of

naturally occurring plant-based agents can open new

strategies for the management of cancer (Nahata et al.,

2013; Shafi et al., 2012). Moreover, it has to be noted that the

use of non-conventional medicines, especially herbal medi-

cine, is still common in cancer patients as approximately 89%

of patients use different alternative therapies, often herbal

and natural products (Miroddi et al., 2011; Tomasin &

Gomes-Marcondes, 2011).

Traditional herbalism has been a pioneering specialty in

biomedical science and utilization of herbal medicine may

become potential treatments also in the future (Shafi et al.,

2012; Susanti et al., 2012). Therefore, studies aimed at

screening natural plants for anticancer properties seem to be

a promising area of investigation and in this context, the

ethnopharmacological knowledge can be helpful to lead the

search for plants with potential cytotoxic activity (Berdowska

et al., 2013; Galvez et al., 2003).

In the present review article, we devoted our attention to a

number of natural herbal remedies that have been traditionally

used to treat the cancer symptoms by Estonian parents.

Estonian people have long traditions in the use of medicinal

plants and over 500 different species are applied in our folk

medicine during the period of 1888–1994 (Raal et al., 2013).

To compile these data, the authors worked through two

massive databases. First, more than 30 000 ethnomedicinal

texts stored in the Estonian Folklore Archives were critically

reviewed. This material has been collected over a period of

150 years to ascertain the rate of the use of different methods

and forms of folk remedies, such as plants, animal remedies,

food, minerals, and chemical substances (Raal & Soukand,

2005). There are two catalogues available in this archive. The

catalogue of folk medicine contains varied information

(ca. 20 000 index cards) about all kinds of folk treatments

being systematized according to the classification of common

diseases. The catalogue of folk botany comprises material

about medicinal plants (ca. 13 000 index cards) that is divided

into different groups (herbaceous plants, shrubs, trees and

bushes, algae, mosses and lichens, mushrooms, etc.) (Soukand

and Raal, 2005). Second, the electronic database HERBA

(http://herba.folklore.ee/) was used. Although this database is

mainly composed using the data from the Estonian Folklore

Archives, its last version contains also the materials from the

twentieth century that are not available in the archive index

cards (Soukand & Raal, 2008).

During the analysis of original records, data about

malformations growing in skin were omitted as the distinction

of malignant neoplasms from different benign disorders based

on the folk medicinal descriptions was rather impossible.

In all other cases, reviewing the data by exact tumor location

was also not feasible as the diagnosis was often delimited only

as ‘‘internal cancer’’. However, as a result of this thorough

analysis, we present 44 different plants used in the Estonian

ethnomedicine to treat the cancerous diseases and relieve

their symptoms. These species include 2 mushrooms,

1 lichen, 25 herbs, 3 berries, 7 vegetables, 1 fruit, and

5 trees. The antitumor application of more than half of these

species is repeatedly reported (Figure 1). The list of all natural

anticancer remedies used and documented in Estonian

ethnomedicinal data collections, together with their applica-

tion modes can be found in Table 1.

Mushrooms

Medicinal mushrooms have an established history to use in

nutritionally functional food as well as traditional therapies.

Traditional medicines derived from medicinal mushrooms

are increasingly being used to treat a wide variety of clinical

conditions (Youn et al., 2009) and anticancer studies of

active ingredients extracted from mushrooms have become

a research hotspot in the recent years (Zhong et al., 2011).

Indeed, approximately 700 species of medicinal mushrooms

have been found to inhibit the growth of different kinds

of cancers (Lemiezek et al., 2011).

In Estonian folk traditions, two mushrooms have been used

to treat various malignancies, whereas the most often cited

anticancer remedy in the Estonian ethnomedicinal database

on the whole is Inonotus obliquus (Fr.) Pilat

(Hymenochaetaceae) (Figure 1).

I. obliquus, called chaga or tchaga in Russia and

kabanoanatake in Japan, is a traditional and widely used

multifunctional mushroom that preferably inhabits as para-

sitism on living trunks of the mature birch (Handa et al.,

2010; Song et al., 2013). From about 20 thousand plants, only

one can be found to have I. obliquus making its price rather

stiff. It is distributed in colder northern climates: in eastern

Russia, northeast China, Hokkaido in Japan, and other

countries located at latitudes of 45–50�N (Hu et al., 2009;

Song et al., 2013). The sclerotia of this mushroom have been

Inonotu

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Figure 1. Plants used as natural anticancer remedies that are reportedmore than once in the Estonian ethnomedicinal databases.

2 K. Sak et al. Pharm Biol, Early Online: 1–12

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used as a folk remedy to treat cancer patients in Russia,

Poland and most of the Baltic countries already since the

sixteenth century. In 1955, the Medical Academy of Science

in Moscow announced I. obliquus as an anticancer substance,

and it was later approved by the government to be used for the

development of pharmaceuticals. Commercial patent medi-

cine called Befungin is still used in cancer prevention and

palliative treatment in this region (Lemiezek et al., 2011;

Song et al., 2013). A decoction of sclerotia of I. obliquus is

non-toxic to normal cells and several pharmacological studies

have shown its antitumor activity against different malig-

nancies, such as lung, breast, uterine, gastric, colon, and liver

cancer as well as leukemia and melanoma (Lee et al., 2009;

Lemiezek et al., 2011; Nomura et al., 2008; Won et al., 2011).

I. obliquus is traditionally taken mainly in the form of a hot

water extract; however, some significant differences can exist

between the chemical compositions of hot water and ethanol

extracts (Hu et al., 2009).

In recent years, more than 20 different kinds of bioactive

components have been found in I. obliquus, including

triterpenoids, polyphenols, steroids, b-glucan, peptides, and

polysaccharides, suggesting a high medicinal value and

good prospects for market development (Hu et al., 2009;

Song et al., 2013). Triterpenoids such as inotodiol,

lanosterol, and trametenolic acid are considered the main

antitumor ingredients being able to induce growth inhibition,

cell cycle arrest, and apoptosis in different cancer cells;

however, the exact molecular mechanisms by which

these effects occur are still not well understood (Chung

et al., 2010; Du et al., 2011; Nomura et al., 2008; Youn et al.,

2009; Zhong et al., 2011). Polysaccharides from I. obliquus

can indirectly be involved in anticancer processes mainly

via stimulating the immune system (Lee et al., 2009;

Song et al., 2013). Immunotherapy through activation of a

host immune system can indeed be a good alternative

method for cancer control (Kim et al., 2006). Having an

inhibitory effect on various tumor cells, I. obliquus might

prevent the metastasis and recurrence of malignancy; more-

over, it can also improve the patient’s tolerance during

chemotherapy or radiotherapy and weaken the adverse

Table 1. Plants used in the Estonian folk medicine for cancer treatment and their application mode.

English name Latin name No. of citations Application mode in Estonian folk medicine

Chaga Inonotus obliquus 96 Herb tea; extract in ethanol or in waterWormwood Artemisia absinthium 16 Herb tea; extract in ethanol or in waterHorseradish Armoracia rusticana 12 Raw chopped root; extract of chopped root in ethanolGarlic Allium sativum 10 Chopped bulb with honey; extract of chopped bulb in ethanolFly agaric Amanita muscaria 9 Raw mushrooms; tincture in ethanolRed clover Trifolium pretense 9 Herb tea from flowersWild Angelica Angelica sylvestris 9 Herb tea from flowers and roots; bath from root extractAloe Aloe vera 8 Extract in ethanol or in wine; pure plant fluid with honeySweet flag Acorus calamus 7 Herb tea or powder from rhizomesOak Quercus robur 7 Herb tea from barkNettle Urtica dioica 5 Raw herb; herb teaBirch Betula pendula 5 Herb tea from bark; extract of buds in ethanolYarrow Achillea millefolium 4 Herb tea; extract in ethanolGreater plantain Plantago major 4 Herb teaWater pepper Polygonum hydropiper 4 Herb teaStonecrop Sedum acre 4 Herb teaLingonberry Vaccinium vitis-idaea 4 Herb tea from stemMarigold Calendula officinalis 3 Herb tea from flowersSt. John’s wort Hypericum perforatum 3 Herb teaCelandine Chelidonium majus 3 Herb tea from the dried whole plant with rootsChamomile Matricaria recutita 2 Herb teaFlax Linum usitatissimum 2 Boiled water extract of seedsOnion Allium cepa 2 Chopped bulb with honeyRed pepper Capsicum annuum 2 Extract in ethanolPine Pinus sylvestris 2 Herb tea or ethanol extracts from young green needlesIceland moss Cetraria islandica 1 Herb teaColtsfoot Tussilago farfara 1 Herb teaBurdock Arctium lappa 1 Herb tea from rootsElecampane Inula helenium 1 Extract of roots in waterBird’s-foot trefoil Lotus corniculatus 1 Herb teaField horsetail Equisetum arvense 1 Herb teaRye grass Secale cereale 1 Herb tea from sproutsWild thyme Thymus serpyllum 1 ExhalationWater lily Nymphaea alba 1 Herb tea from dried flowersBittersweet Solanum dulcamara 1 Boiled water extractCota tinctoria Anthemis tinctoria 1 Herb teaBilberry Vaccinium myrtillus 1 Fruits; herb tea from stemsStrawberry Fragaria vesca 1 Fluid from whole plant dissolved in ethanolRadish Raphanus sativus 1 Extract obtained by keeping honey in the hole of taprootBeetroot Beta vulgaris 1 Juice of raw rootsCarrot Daucus sativus 1 Juice of raw rootsLemon Citrus limon 1 Extract of fruit in waterRowan Sorbus aucuparia 1 Herb tea from barkBird cherry Prunus padus 1 Herb tea from powder of dried berries

DOI: 10.3109/13880209.2013.871641 Estonian ethnomedicinal anticancer experiences 3

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side effects of these traditional treatment modalities (Song

et al., 2013).

There are essentially less data published about the potential

anticancer properties of another mushroom used in Estonian

folk traditions, Amanita muscaria (L. ex Fr.) Hooker

(Amanitaceae) or fly agaric. However, Kiho et al. (1994)

have shown that water soluble carboxymethylated (1!3)-a-D-

glucan isolated from the extract of its fruiting bodies exhibits

potent antitumor activity against sarcoma 180 in mice.

Lichens

The only lichen used as an anticancer remedy in Estonian folk

traditions is Cetraria islandica (L.) Ach. (Parmeliaceae),

commonly known as Iceland moss.

Cetraria islandica has been used for centuries in folk

medicine in many countries against a number of conditions,

mainly as an aqueous extract. It has been used not only for

the treatment of minor ailments such as throat irritation and

cough but also for tuberculosis, asthma, and gastrointestinal

conditions such as gastritis, and gastric and duodenal ulcers

(Freysdottir et al., 2008; Ingolfsdottir et al., 1997). No toxic

effects or drug interactions are reported for the use of this

lichen (Freysdottir et al., 2008).

Different compounds are isolated from Cetraria islandica,

some of which have an established biological activity. This

lichen has high proportions of polysaccharides of which

lichenan and isolichenan are shown to exert antitumor activity

on the implanted sarcoma 180 in mice (Fukuoka et al., 1968).

Lichenan, which is a b-glucan, has also immunomodulatory

effect when tested in vitro in dendritic cell model (Freysdottir

et al., 2008). Cetraria islandica also contains several

secondary metabolites, including protolichesterinic acid.

This compound exhibits marked antiproliferative effects on

human breast carcinoma and leukemia cell lines

(Ogmundsdottir et al., 1998) and exerts also antitumor

activity against Ehrlich carcinoma in mice. Furthermore,

protolichesterinic acid has found to possess strong antibac-

terial properties against Helicobacter pylori, the organism

contributing to the etiology of gastritis, gastric, and duodenal

ulcers, but also to certain forms of gastric cancer (Freysdottir

et al., 2008; Ingolfsdottir et al., 1997). The reputed beneficial

effects of Cetraria islandica in cases of gastric malignancies

could, therefore, be due, at least in part, to the inhibitory

activity of protolichesterinic acid against H. pylori.

Cetraria islandica is also a potential source of natural

antioxidants (Gulcin et al., 2002) allowing defense against

oxidative stress and being thus important for cancer

prevention.

Herbs

The use of 25 different herbs against malignant disorders

is described in Estonian ethnopharmacological data

archive (Table 1). Among them, eight plants belong to the

Asteraceae family. Artemisia absinthium L. (Asteraceae)

(wormwood), Achillea millefolium L. (Asteraceae) (yarrow),

Calendula officinalis L. (Asteraceae) (marigold), and

Chamomilla recutita (L.) Rauschert (Asteraceae) (chamo-

mile) have all been commonly used as herbal tea to treat and

relieve the symptoms of cancer diseases by our parents.

Experimental in vitro data show that the extract of Artemisia

absinthium can induce the antiproliferative effects on both

estrogen-responsive and -unresponsive human breast cancer

cell lines (Shafi et al., 2012) and possess antileukemic

properties on human T leukemia cells (Wegiera et al., 2012).

Activity against leukemia has described also for Achillea

millefolium, in which case the three new compounds,

achimillic acids A, B, and C, are isolated and found to be

active against mouse leukemia cells (Tozyo et al., 1994). This

herb has shown significant cytotoxicity also for several human

liver cancer cells being more active on non-hepatitis B virus

genome-containing lines (Ghavami et al., 2010; Lin et al.,

2002). Another novel compound, achillinin A, is purified

from yarrow and exhibits potential antiproliferative activity to

various human lung cancer cell lines (Li et al., 2011). Cancer-

suppressive action has reported also for Calendula officinalis

whereas the laser-activated Calendula extract induces growth

inhibitory effect in various human and murine cancer cell

lines (Jimenez-Medina et al., 2006). Triterpene glycosides

isolated from marigold flowers exhibit the potent cytotoxic

activity against human colon cancer, leukemia, and melanoma

cells (Ukiya et al., 2006) and the flower extract can suppress

the metastatic spread of melanoma cells to lung in mice

(Preethi et al., 2010). Cytotoxic action of marigold tea is

highly selective to target cancer cells being similar to the

effect of chamomile tea; however, marigold tea exhibits

significantly stronger cytotoxic action against malignant cell

lines in comparison to chamomile tea (Matic et al., 2013;

Srivastava & Gupta, 2007). In recent years, different extracts

of Chamomilla recutita have shown to suppress the growth of

various human malignant cell lines, such as prostate, cervical,

colon, and breast cancer as well as leukemia cells (Kogiannou

et al., 2013; Matic et al., 2013; Srivastava & Gupta, 2007,

2009). Besides the extraction techniques many other factors

may play role in the biological activity of chamomile,

including climatic and seasonal changes, harvest time, and

storage conditions, whereas the major bioactive compound

possessing anticancer activity in chamomile extract might be

apigenin (Srivastava & Gupta, 2009). Commercial samples of

chamomile tea from Estonia and other countries contained

0.4–9.3 mg of apigenin glucoside and 0–1.5 mg apigenin

acetylglucoside per cup (200 ml) of tea (Raal et al., 2012).

Apigenin glucoside was also found (1.4–8.3 mg/ml) in

Chamomilla suaveolens (Pursh) Rydb. (Asteraceae) (pine-

apple weed) flowers growing widely in Estonia and used

in our ethnomedicine (Raal et al., 2011).

Other species from the Asteraceae family have mentioned

only once in our folk traditional database with respect to their

anticancer properties. Although the flower buds of Tussilago

farfara L. (Asteraceae), commonly called coltsfoot, have

mainly used for the treatment of several benign pulmonary

diseases, such as bronchitis and asthmatic conditions

(Dobravalskyte et al., 2013; Lee et al., 2008), compounds

isolated from this herb can inhibit also mouse lung cancer

cells (Liu et al., 2009) and its extract has shown to induce

cytotoxic activity against human colon cancer cells (Lee et al.,

2008). However, besides these beneficial effects, caution

has to be adopted in the use of coltsfoot as it can be itself

carcinogenic due to the content of hepatotoxic pyrrolizidine

alkaloids, mainly senkirkine (Dobravalskyte et al., 2013;

4 K. Sak et al. Pharm Biol, Early Online: 1–12

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Hirono et al., 1976). In contrast, roots of Arctium lappa L.

(Asteraceae) (burdock) have hepatoprotective activities (Chan

et al., 2011; Predes et al., 2011) and extract of this herb has

shown antiproliferative effects on various cancer cells (Predes

et al., 2011; Wegiera et al., 2012). Purification of active

compound from the seed extract of Arctium lappa has led to

the identification of lignan arctigenin as tumor-specific agent

showing cytotoxicity to gastric, liver, colon, starved pancreas,

and lung cancer as well as leukemia cells (Awale et al., 2006;

Chan et al., 2011; Matsumoto et al., 2006; Predes et al., 2011;

Susanti et al., 2012). A remarkable antineoplastic activity has

demonstrated also for the extract prepared from Inula

helenium L. (Asteraceae) roots revealing toxicity toward

different tumor cell lines, including gastric, colon, liver,

pancreas, mammary, and cervical cancer as well as astro-

cytoma, leukemia and melanoma cells (Dorn et al., 2006).

Several sesquiterpene lactones with anticancer properties

such as isocostunolide and helenin have isolated from this

plant (Chen et al., 2007a; Konishi et al., 2002; Spiridonov

et al., 2005), whereas the cytotoxic activity of helenin on

human lymphoblastoid cells even exceeds that of the known

pharmaceutical drugs cyclophosphamide and fluorouracil and

approaches the activity of methotrexate (Spiridonov et al.,

2005). Lack of mutagenicity of Inula helenium extract further

strengthens its chances for being eventually used in cancer

therapy (Dorn et al., 2006).

Two species used in Estonian ethnomedicine for alleviat-

ing the symptoms of cancer patients represent the

Papilionaceae family. The majority of studies on the bio-

logical properties of Trifolium pratense L. (Fabaceae)

(red clover) are focused on its phytoestrogenic action, being

a result of isoflavone content (Kolodziejczyk-Czepas, 2012).

These phytoestrogens can inhibit angiogenesis and red

clover extract might be a powerful chemopreventive agent

(Kolodziejczyk-Czepas, 2012; Krenn & Paper, 2009). Dietary

isoflavones derived from red clover may also halt the

progression of prostate cancer by inducing apoptosis in low

to moderate-grade tumors with only minimal adverse effects

(Jarred et al., 2002; Kolodziejczyk-Czepas, 2012). Extract of

the other herb from Papilionaceae family, Lotus corniculatus

L. (Fabaceae) (bird’s-foot trefoil) may also be a potential

antitumor agent inhibiting the viability of macrophage-like

murine tumor cells (Reza et al., 2012).

Potential anticancer properties of some other herbs are

also relatively often described in Estonian folk traditions

(Figure 1). Among them, Aloe vera (L.) Burm.f. (Aloaceae)

(aloe) is a genus of medicinal plants with a history of medical

use for several thousand years (Boudreau et al., 2013; Harlev

et al., 2012). Its antineoplastic property is due to at least three

different mechanisms based on antiproliferative, immunosti-

mulatory, and antioxidant effects, whereas the antiprolifera-

tive action is determined mainly by the anthraquinonic

molecules, such as aloin and emodin (Harlev et al., 2012).

Aloin, an anthraquinone glycoside derived from aloe leaves,

has shown to inhibit human cervical, breast, and ovarian

cancer cells as well as leukemia cells, exerting also

antiangiogenic properties (Harlev et al., 2012; Niciforovic

et al., 2007; Pan et al., 2013). Aloe emodin might represent a

suitable antitumor drug candidate for the treatment of various

human cancers, such as colon, gastric, bladder, lung, tongue,

nasopharyngeal, uterine, and liver carcinoma, neuroectoder-

mal tumor, leukemia, Ewing’s sarcoma, neuroblastoma, and

glioma (Acevedo-Duncan et al., 2004; Chen et al., 2007b;

Harlev et al., 2012; Ismail et al., 2013; Pecere et al., 2000).

However, only limited data are available on the safety of Aloe

vera supplements leaving this issue controversial and uncer-

tain. Few reports have even shown that aloe leaf extract can

itself exert some carcinogenic activity (Ahlawat & Khatkar,

2011; Boudreau et al., 2013). Aloin and aloe emodin were

found in roots and petioles of Rheum rhaponticum L.

(Polygonaceae) (dietary rhubarb) cultivated in Estonia, but

not mentioned in folk medicine as the anticancer herbal

remedy (Pussa et al., 2009).

Another plant well known for its therapeutic properties

already since antiquity is Hypericum perforatum L.

(Clusiaceae), commonly called St. John’s wort. It is even

considered as a bridge between the conventional and the

alternative medicine (Istikoglou et al., 2010; Klemow et al.,

2011). Different extracts of this plant are reported to induce

growth arrest of malignant cells, such as leukemia, melanoma,

prostate, and breast cancer cells (Ferguson et al., 2011;

Hostanska et al., 2002, 2003; Martarelli et al., 2004;

Menichini et al., 2013; Roscetti et al., 2004). Two major

biologically active constituents have identified: hyperforin

and hypericin (Hostanska et al., 2003; Klemow et al., 2011).

Hyperforin has shown to exert antiproliferative activities

toward various human and rat cancer cells in vitro being

capable of inhibiting the growth of mammary tumor cells also

in vivo (Billard et al., 2013; Hostanska et al., 2003; Schempp

et al., 2002). This compound might be an attractive broad-

spectrum anticancer reagent with activity against a wide

range of different tumors (Billard et al., 2013; Klemow et al.,

2011; Schempp et al., 2002). The other active constituent

isolated from H. perforatum, hypericin, can also inhibit the

growth of cells derived from a variety of neoplastic tissues;

activity of this compound is attributed to its photocytotoxic

properties and hypericin can be used as a component of

photodynamic therapy (Hostanska et al., 2002; Klemow

et al., 2011; Menichini et al., 2013; Ocak et al., 2013; Roscetti

et al., 2004). Both compounds can work also in cooperation,

to impede the growth of malignant cells synergistically,

making H. perforatum an interesting option in cancer

treatment and clearly warranting further investigations to

evaluate their action (Hostanska et al., 2003; Klemow et al.,

2011). Both H. perforatum and Hypericum maculatum Crantz

(Clusiaceae) are common species throughout Estonia and

neighboring countries and were used in ethnomedicine.

H. maculatum contained about a 2.5 times more hypericin

(141–228 mg%) than H. perforatum (75–81 mg%) and could

thus be a good natural source of hypericin (Raal et al., 2010).

More work is needed also to study the anticancer

properties of Chelidonium majus L. (Papaveraceae) (greater

celandine). This plant extract and its derivatives have

potential of being successfully used as a therapeutic agent

against leukemia and melanoma as well as lung, liver,

pancreas, pelvic, cervical, prostate, and breast cancers

(Aljuraisy et al., 2012; Kulp & Bragina, 2013; Nadova

et al., 2008; Paul et al., 2012, 2013). Chelidonium majus is

rich in various types of isoquinoline alkaloids, including

chelidonine that has shown promising antitumor potential

DOI: 10.3109/13880209.2013.871641 Estonian ethnomedicinal anticancer experiences 5

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with the ability to overcome multidrug resistance of different

cancer cell lines and might be, therefore, profitable in medical

oncology. However, its poor oral bioavailability makes the

optimal use rather limited. It is only recently demonstrated

that nanoparticles mediated chelidonine delivery can be an

attractive alternative and promising approach for cancer

treatment (Paul et al., 2013).

Urtica dioica L. (Urticaceae), known as nettle, is also a

frequently used herb in cancer therapy, whereas both roots

and leaves of this plant are consumed in traditional medicine

(Durak et al., 2004; Guler, 2013). Its extracts have shown

significant anticancer activity against human prostate, breast,

and colon cancer cells (Aydos et al., 2011; Durak et al., 2004;

Guler, 2013; Konrad et al., 2000). Cytotoxicity toward several

human cancer cell lines has demonstrated also for extracts

prepared from Equisetum arvense L. (Equisetaceae) (field

horsetail) and Secale cereale L. (Poaceae) (rye grass)

(Cetojevic-Simin et al., 2010; Moodley & Shengwenyana;

Sandhu et al., 2010); however, anticancer effects and potential

oncological applications of these plants certainly need further

investigation.

The growth of breast adenocarcinoma as well as melan-

oma cells can be suppressed by Plantago major L.

(Plantaginaceae) (greater plantain) extracts (Galvez et al.,

2003). Furthermore, this widespread plant can inhibit trans-

plantable, experimental Ehrlich ascites carcinoma in mice

preventing thus the tumor extension (Ozaslan et al., 2007,

2009). Some cytotoxic activity against both estrogen-

dependent and -independent human breast cancer cells but

not normal breast cells has described also for Thymus

serpyllum L. (Lamiaceae) (wild thymus) extracts representing

thus a promising candidate in the development of novel

therapeutic drugs for breast cancer treatment (Berdowska

et al., 2013; Bozkurt et al., 2012). However, it is still

important to mention that the chemical composition of

Thymus serpyllum samples from Estonia and other countries

varied to a large extent (Paaver et al., 2008).

Progression of breast cancer can be slowed down also by

dietary intake of flaxseeds, whereas the antiestrogenic activity

of phytoestrogens, such as lignans and isoflavones, found

abundantly in Linum usitatissimum L. (Linaceae) (flax), may

contribute to this effect (Lowcock et al., 2013; Marghescu

et al., 2012; Theil et al., 2013).

Marked efficacy against human cervical adenocarcinoma

cells has been described for Polygonum hydropiper L.

(Polygonaceae) (water pepper) (Lajter et al., 2013). Active

agents of Nymphaea alba L. (Nymphaeaceae) (water lily) can

inhibit the process of renal tumor formation (Khan &

Sultana, 2005). Rhizome of Acorus calamus L. (Acoraceae)

(sweet flag) might be also a potential source of metabolites

with anticancer properties as its extracts are antiproliferative

toward several human breast and liver carcinoma cells

(Rajkumar et al., 2009). Moreover, one of the active

components of this traditional herb, b-asarone, has been

recently described to inhibit colorectal carcinogenesis by

inducing cellular senescence (Liu et al., 2013). Some

cytotoxic activity on human colon cancer cells has shown

also for Sedum acre L. (Crassulaceae) (stonecrop) extract;

however, this antiproliferative effect reveals only at relatively

high concentrations (Stankovic et al., 2012). Despite its

wide use in folk medicine, only very few published data

are available also for the tumor inhibitory effect of

Solanum dulcamara L. (Solanaceae) (bittersweet). It is

almost 50 years ago when the anticancer activity of this

herb extract against sarcoma in mice has described and

the bioactive alkaloid glycoside b-solamarine isolated

(Kupchan et al., 1965).

To the best knowledge of authors, no data about the

potential anticancer properties of two herbs used in Estonian

folk traditions for the treatment of cancer symptoms are

published so far: Anthemis tinctoria L. (Asteraceae) and

Angelica sylvestris L. (Apiaceae). Based on the Estonian

ethnomedicinal experiences, these herbs certainly deserve

further investigations and the respective experiments are

already in work.

Berries

Our Estonian parents have used three different berry plants to

treat and relieve various cancer symptoms. Herb tea

from stems of lingonberries and bilberries and ethanol

extract of strawberry plants have prepared and utilized in

combating tumors; also, raw bilberry fruits have been eaten as

medicine.

Throughout history, berries have been an important and

valued part of the human diet (Chu et al., 2011). They contain

a diverse range of phytochemicals that have proposed to exert

anticarcinogenic properties, mainly polyphenolic compounds,

and a wide number of laboratory and animal studies have

indeed shown the anticancer action of different fruit extracts

(Misikangas et al., 2007; Mutanen et al., 2008; Seeram et al.,

2006; Somasagara et al., 2012; Weaver et al., 2009). Thus,

berries can be considered as promising functional foods for

reducing the cancer risk (Katsube et al., 2003). Reports

focusing on the chemopreventive effects of Vaccinium vitis-

idaea L. (Ericaceae) (lingonberry) fruits are rather limited.

Lingonberry fruit extract has described to exert cytotoxic

activity on human leukemia, breast, cervical and colon

cancer cell lines, and inhibit the formation and growth of

murine intestinal adenoma (Misikangas et al., 2007; Mutanen

et al., 2008; Wang et al., 2005). Antiproliferative effects

of these fruits are largely caused by proanthocyanidins,

however, their action mechanism is as yet unknown

(McDougall et al., 2008).

Extracts of Vaccinium myrtillus L. (Ericaceae) (bilberry,

also known as European blueberry) have been found to be

effective for inhibiting the growth of human leukemia, colon,

and breast carcinoma cell lines as well as decreasing the

number of intestinal adenoma in rats (Chu et al., 2011; Faria

et al., 2010; Nguyen et al., 2010; Wu et al., 2007). The growth

inhibitory and cytotoxic activity of bilberry fruit extracts on

cancer cells are likely attributed to phenolic pigments, the

anthocyanins, as bilberry fruits are one of the richest natural

sources of these flavonoids and consumption of berries is the

predominant means of anthocyanin ingestion (Chu et al.,

2011; Katsube et al., 2003; Nguyen et al., 2010). Anticancer

effects of bilberry fruit extract on breast tumor cells are

probably independent on estrogen receptor expression as the

growth of both estrogen responsive and unresponsive cell

lines is suppressed (Faria et al., 2010).

6 K. Sak et al. Pharm Biol, Early Online: 1–12

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The phytochemicals present in extracts prepared from

fruits of different strawberry cultivars [Fragaria vesca L.

(Rosaceae)] have been found to display inhibitory effects on

human leukemia, liver, colon, cervical, and breast cancer cells

and interfere the progression of murine breast adenocarcin-

oma (McDougall et al., 2008; Meyers et al., 2003; Olsson

et al., 2006; Seeram et al., 2006; Somasagara et al., 2012).

Strawberries have high therapeutic potential acting as both

chemopreventive and therapeutic agents, whereas the main

effectiveness could be due to their high content of

ellagitannins (McDougall et al., 2008; Olsson et al., 2006;

Somasagara et al., 2012). Different cultivars have significant

differences in the content of anticancer phytochemicals and

inhibit thus the proliferation to diverse extents; moreover,

the contents of active compounds can vary also in response

to different environmental conditions such as temperature,

water availability, pathogenic attack, and nutrients (Meyers

et al., 2003; Olsson et al., 2006).

The majority of studies on the anticancer activity of berries

are performed using extracts prepared from fruits. However,

the content of bioactive compounds in berry stems and fruits

can be largely different and based on the application mode

of lingonberries, bilberries, and strawberries as anticancer

remedies in Estonian ethnomedicine further investigation

of potential effects of stem extracts is needed. On one hand,

it is indeed shown that anthocyanins are mainly found in

the deeply colored fruits and not leaves of bilberry (Chu

et al., 2011), and on the other hand, the non-edible parts of

strawberry has found to be richer in ellagic acid than ripe

fruits, whereas young leaves have higher total phenolic

content than the respective fruits and old leaves (Skupien

et al., 2006). It is clear that phytochemicals present in various

parts of berry plants are of high interest in the search of new

antitumor drugs and their laboratory studies must be certainly

continued.

Vegetables and fruits

Literature has shown very strong evidence that consumption

of fruits and vegetables can protect against a wide variety

of cancers (Shrivastava & Ganesh, 2010; Wu et al., 2007).

Fruits and vegetables contain an incredible diversity of

bioactive phytochemicals and old Estonians have traditionally

used several culinary herbs in combating malignancies.

Knowledge about these remedies is stored up in our

ethnomedicinal data archives.

Seven different vegetables (garlic, onion, horseradish and

radish, pepper, beetroot, and carrot) and one fruit (lemon) are

used by our parents for treating and relieving symptoms

caused by various tumors. Cytoprotective effects on normal

cells and cytotoxicity toward tumor cells have shown in the

case of allium vegetables (Shrivastava & Ganesh, 2010).

Interest in the potential benefits of these vegetables has its

origin in antiquity (Galeone et al., 2006). Indeed, Allium

sativum L. (Alliaceae) (garlic) is among the oldest medicinal

plants used by different people in all over the world. It has

been applied for medicinal purpose already for more than

3000 years being also one of the first plants with constituents

reported to possess antitumor properties (Miroddi et al.,

2011; Omar & Al-Wabel, 2010; Shukla & Kalra, 2007;

Tsubura et al., 2011). Also, the bulb of Allium cepa L.

(Alliaceae) (onion) has been consumed medicinally for many

centuries (Wang et al., 2012) and the use of both garlic and

onion in traditional medicinal practice seems to be very safe

(Votto et al., 2010). Garlic may be classified as a dietary

anticarcinogen on the basis of epidemiological and experi-

mental investigations, whereas its beneficial action is not

limited to a specific species, particular anatomical locations

or specific carcinogens (Khanum et al., 2004; Shukla &

Kalra, 2007). Thus, garlic extracts have been shown to inhibit

the growth of human breast, uterine, prostate, kidney, lung,

liver, esophagus, stomach, colon, and skin cancer as well as

neuroblastoma, leukemia, and melanoma cells (Galeone et al.,

2006; Herman-Antosiewicz et al., 2007; Khanum et al., 2004;

Milner, 2006; Miroddi et al., 2011; Omar & Al-Wabel, 2010;

Shukla & Kalra, 2007; Tsubura et al., 2011). Onion has shown

even better inhibitory activity against tumor cells than garlic

(Shrivastava & Ganesh, 2010; Sohail et al., 2011) suppressing

the growth of colorectal, liver, laryngeal, ovarian, and blood

cancer cells (Galeone et al., 2006; Votto et al., 2010; Wang

et al., 2012; Yang et al., 2004). The anticarcinogenic effects of

allium vegetables are attributed to their organosulfur ingre-

dients (Galeone et al., 2006; Herman-Antosiewicz et al.,

2007). Garlic contains a complex mixture of organosulfur

compounds that are generated upon its processing; the

presence of several other factors, including selenium and

flavonoids, may also account for its tumoricidal action

(Milner, 2006; Miroddi et al., 2011; Omar & Al-Wabel,

2010; Tsubura et al., 2011). The content of organosulfur

compounds is high also in onions; moreover, onions are one

of the richest sources of flavonoids in the human diet and the

different constituents probably exert an additive action in

destroying cancer cells (Galeone et al., 2006; Votto et al.,

2010; Wang et al., 2012; Yang et al., 2004). Furthermore,

different onion varieties have broad variability in their

contents of bioactive agents depending also on the genetic,

agronomic, and environmental factors, leading to a significant

variation in the antiproliferative activities among the onion

varieties (Yang et al., 2004).

Armoracia rusticana G. Gaertn., B. Mey. & Scherb.

(horseradish) and Raphanus sativus L. (radish) are two

vegetables belonging to the Brassicaceae family. Extracts

prepared from radish root have been described to exert

potential cytotoxic activity toward several human cancer cell

lines (cervical, lung, breast, and prostate carcinoma cells) and

this tumoricidal action has been attributed to its isothiocyan-

ates content. Different varieties of R. sativus have genetic

variability that besides the environmental factors might affect

the content and types of isothiocyanates in radish root (Beevi

et al., 2010). The phytochemical profiles of other parts of this

plant (stems, leaves, and seeds) differ significantly from their

bioactive ingredients; however, they can also exhibit signifi-

cant anticancer activities: extracts prepared from aerial parts

inhibit the growth of human breast cancer cells (Kim et al.,

2011), sprouts exert some protective activity against colon

cancer (Beevi et al., 2010), and seed extracts have strong

cytotoxic effects on human colon, liver, cervical, and breast

cancer cells (Abd-Elmoneim et al., 2013). Some compounds

with potential anticancer properties are isolated also from

horseradish extracts (Weil et al., 2005).

DOI: 10.3109/13880209.2013.871641 Estonian ethnomedicinal anticancer experiences 7

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Tumor-specific cytotoxicity against human cancer cell

lines has been described also for Capsicum annuum L.

(Solanaceae) (Motohashi et al., 2003). A pungent bioactive

ingredient in varieties of Capsicum annuum (red pepper) is

capsaicin and its antitumor activities have reported in various

malignant cells, such as human esophageal, gastric, cervical,

ovarian, breast, prostate, and liver carcinoma as well as

leukemia and melanoma cells (Huang et al., 2009; Lo et al.,

2005; Mori et al., 2006; Wu et al., 2006; Zhang et al., 2003).

In the case of prostate cancer, capsaicin can inhibit both

androgen-sensitive and -insensitive tumors pointing to its

potential role in the management of prostate cancer

patients, refractory to hormonal therapies (Mori et al.,

2006). At the same time, the root extract of Beta vulgaris

L. (Chenopodiaceae) (beet) can inhibit the growth of

hormone-dependent human breast cancer cells (Tripathy &

Pradhan, 2013) and taproot juice of Daucus sativus Hort.

Ex Passerini (Apiaceae) (carrot) may be an excellent source

of bioactive chemicals for the treatment of different leukemias

affecting somewhat stronger lymphoid than myeloid malig-

nancies (Zaini et al., 2011, 2012).

The only fruit consciously used in Estonian ethnomedicine

for the treatment of cancer symptoms is Citrus limon (L.)

Burm.f. (Rutaceae) (lemon). Its fruit extract has indeed

reported to exhibit anticancer activity against human

breast cancer cells (Alshatwi et al., 2011); whereas essential

oils isolated from lemon peels exert cytotoxic effects

on human colorectal, breast and cervical cancer cell lines

(Jomaa et al., 2012).

Trees

Herbal teas prepared from bark of Quercus robur L.

(Fagaceae) (oak), Betula pendula Roth (Betulaceae) (birch)

or Sorbus aucuparia L. (Rosaceae) (rowan) have all used

in Estonian ethnomedicinal practice for the treatment of

cancerous diseases. The extracts of buds of Betula pendula,

young green needles of Pinus sylvestris L. (Pinaceae) (pine)

and powdered dried berries from Prunus padus L. (Rosaceae)

(bird cherry) have also applied to relieve the various

complaints characteristic to various tumors.

Bark extracts prepared from birch tree exert antiprolifera-

tive effects against various human cancer cell lines, including

skin, ovarian, cervical, and breast carcinomas (Dehelean

et al., 2012). Valuable anticancer agents in the birch tree bark

are pentacyclic triterpenes, mainly betulin and betulinic acid

(Dehelean et al., 2012; Soica et al., 2012). Extract prepared

from oak has also reported to exhibit tumoricidal activity

inhibiting the growth of murine leukemia cells (Goun et al.,

2002). In contrast, no data about the potential antitumor

activity of Pinus sylvestris, Sorbus aucuparia, and Prunus

padus can be found in the literature, although the use of

all these remedies has clearly reported in the Estonian

ethnomedicinal data collections. This indicates that the future

investigations of anticancer activity of natural extracts should

certainly include the preparations of these trees.

Conclusions and further perspectives

Besides presenting a comprehensive review of traditional

ethnomedicinal remedies for the management of tumors by

old Estonian people, the most important value of this article

is selection of five plants which despite their wide use in

Estonian folk traditions to treat cancerous diseases and relieve

their devastating symptoms are not yet characterized in the

scientific literature. Therefore, it is clear that the potential

anticancer properties of all these species (Angelica sylvestris,

Anthemis tinctoria, Pinus sylvestris, Sorbus aucuparia, and

Prunus padus) need further investigations. These plants are

common and prevalent in Estonia; Wild Angelica, is spread

mostly in Northern and Middle Europe, cota tinctoria is very

common throughout Europe, especially in Scandinavia. Also,

rowan, pine, and bird cherry are distributed over the Europe.

The habitats of pine and bird cherry include also several parts

of Asia where the traditions of investigation of natural

anticancer compounds are much more long lasting and

profound. In this context, the antiproliferative properties

shown for the extracts prepared from several pine (Pinaceae)

species growing in Asia [such as Pinus densata Masters,

Pinus densiflora Siebold & Zucc., Pinus kesiya Royle ex

Gordon, Pinus koraiensis Siebold & Zucc., Pinus massoniana

Lamb., Pinus morrisonicola Hayata, Pinus parviflora Siebold

& Zucc., and Pinus wallichiana A.B. Jacks.] encouraged us to

follow the studies also with Pinus sylvestris.

Different fractions of herbs (aqueous or organic) can

contain different compounds and exhibit different activities.

Moreover, some extracts may exert greater effects than

individual constituents showing that various compounds can

act both in additive and in even synergistic mode and

implying that combinations of phytochemicals present in

plants are crucial for their ultimate biological activities.

Furthermore, contribution of some additional and still

unidentified compounds in such mixtures can also not be

excluded.

The ancient ethnobotanical knowledge is mostly based on

the in depth and long-term empirical experiences with the

locally available natural resources. Many of the traditionally

used plants have not yet been studied scientifically; however,

due to the ongoing need for more effective, more specific,

less toxic, and cheaper anticancer medicines and considering

the fact that almost two-thirds of the anticancer drugs

employed nowadays in the clinical practice are derived from

plant sources, the herbal materials used successfully in

ethnomedicine are certainly worth of further scientific

evaluation and can open one possible way for the future

drug design. Therefore, we have already started with the

studies to investigate the scientific basis of traditional

application of plants described in this review.

Declaration of interest

The authors report no declarations of interest.

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