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

Abstract

Context: Despite diagnostic and therapeutic advancements, the burden of cancer is still increasing worldwide. Toxicity of current chemotherapeutics to normal cells and their resistance to tumor cells highlights the urgent need for new drugs with minimal adverse side effects. The use of natural anticancer agents has entered into the area of cancer research and increased efforts are being made to isolate bioactive products from medicinal plants.

Objective: To lead the search for plants with potential cytotoxic activity, ethnopharmacological knowledge can give a great contribution. Therefore, the attention of this review is devoted to the natural remedies traditionally used for the cancer treatment by Estonian people over a period of almost 150 years.

Methods: Two massive databases, the first one stored in the Estonian Folklore Archives and the second one in the electronic database HERBA (http://herba.folklore.ee/), containing altogether more than 30 000 ethnomedicinal texts were systematically reviewed to compile data about the Estonian folk traditional experiences on natural anticancer remedies.

Results and conclusion: As a result, 44 different plants with potential anticancer properties were elicited, 5 of which [Angelica sylvestris L. (Apiaceae), Anthemis tinctoria L. (Asteraceae), Pinus sylvestris L. (Pinaceae), Sorbus aucuparia L. (Rosaceae), and Prunus padus L. (Rosaceae)] have not been previously described with respect to their tumoricidal activities in the scientific literature, suggesting thus the potential herbal materials for further investigations of natural anticancer compounds.

• Cancer treatment
• ethnomedicine
• natural anticancer drugs

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 acuminata 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 medicine, 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 application modes can be found in Table 1.

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

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 water
Wormwood	Artemisia absinthium	16	Herb tea; extract in ethanol or in water
Horseradish	Armoracia rusticana	12	Raw chopped root; extract of chopped root in ethanol
Garlic	Allium sativum	10	Chopped bulb with honey; extract of chopped bulb in ethanol
Fly agaric	Amanita muscaria	9	Raw mushrooms; tincture in ethanol
Red clover	Trifolium pretense	9	Herb tea from flowers
Wild Angelica	Angelica sylvestris	9	Herb tea from flowers and roots; bath from root extract
Aloe	Aloe vera	8	Extract in ethanol or in wine; pure plant fluid with honey
Sweet flag	Acorus calamus	7	Herb tea or powder from rhizomes
Oak	Quercus robur	7	Herb tea from bark
Nettle	Urtica dioica	5	Raw herb; herb tea
Birch	Betula pendula	5	Herb tea from bark; extract of buds in ethanol
Yarrow	Achillea millefolium	4	Herb tea; extract in ethanol
Greater plantain	Plantago major	4	Herb tea
Water pepper	Polygonum hydropiper	4	Herb tea
Stonecrop	Sedum acre	4	Herb tea
Lingonberry	Vaccinium vitis-idaea	4	Herb tea from stem
Marigold	Calendula officinalis	3	Herb tea from flowers
St. John's wort	Hypericum perforatum	3	Herb tea
Celandine	Chelidonium majus	3	Herb tea from the dried whole plant with roots
Chamomile	Matricaria recutita	2	Herb tea
Flax	Linum usitatissimum	2	Boiled water extract of seeds
Onion	Allium cepa	2	Chopped bulb with honey
Red pepper	Capsicum annuum	2	Extract in ethanol
Pine	Pinus sylvestris	2	Herb tea or ethanol extracts from young green needles
Iceland moss	Cetraria islandica	1	Herb tea
Coltsfoot	Tussilago farfara	1	Herb tea
Burdock	Arctium lappa	1	Herb tea from roots
Elecampane	Inula helenium	1	Extract of roots in water
Bird's-foot trefoil	Lotus corniculatus	1	Herb tea
Field horsetail	Equisetum arvense	1	Herb tea
Rye grass	Secale cereale	1	Herb tea from sprouts
Wild thyme	Thymus serpyllum	1	Exhalation
Water lily	Nymphaea alba	1	Herb tea from dried flowers
Bittersweet	Solanum dulcamara	1	Boiled water extract
Cota tinctoria	Anthemis tinctoria	1	Herb tea
Bilberry	Vaccinium myrtillus	1	Fruits; herb tea from stems
Strawberry	Fragaria vesca	1	Fluid from whole plant dissolved in ethanol
Radish	Raphanus sativus	1	Extract obtained by keeping honey in the hole of taproot
Beetroot	Beta vulgaris	1	Juice of raw roots
Carrot	Daucus sativus	1	Juice of raw roots
Lemon	Citrus limon	1	Extract of fruit in water
Rowan	Sorbus aucuparia	1	Herb tea from bark
Bird cherry	Prunus padus	1	Herb tea from powder of dried berries

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 parasitism 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 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 medicine 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 malignancies, 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, β-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; moreover, it can also improve the patient’s tolerance during chemotherapy or radiotherapy and weaken the adverse 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)-α-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 β-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 antibacterial 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) (chamomile) 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 µg/ml) in Chamomilla suaveolens (Pursh) Rydb. (Asteraceae) (pineapple 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; 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 astrocytoma, 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 alleviating the symptoms of cancer patients represent the Papilionaceae family. The majority of studies on the biological 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, immunostimulatory, and antioxidant effects, whereas the antiproliferative 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, neuroectodermal 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 uncertain. 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 (Püssa 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 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 melanoma cells can be suppressed by Plantago major L. (Plantaginaceae) (greater plantain) extracts (Galvez et al., 2003). Furthermore, this widespread plant can inhibit transplantable, 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, β-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 β-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).

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 adenocarcinoma (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 experimental 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 ingredients (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 isothiocyanates 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 significant 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).

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 malignancies (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 antiproliferative 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.