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Anticancer Properties of Phytochemicals Present in Medicinal Plants of North America

Written By

Wasundara Fernando and H. P. Vasantha Rupasinghe

Submitted: 23 October 2012 Published: 19 June 2013

DOI: 10.5772/55859

From the Edited Volume

Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

Edited by Marianna Kulka

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1. Introduction

Cancer is one of the most severe health problems in both developing and developed countries, worldwide. Among the most common (lung, stomach, colorectal, liver, breast) types of cancers, lung cancer has continued to be the most common cancer diagnosed in men and breast cancer is the most common cancer diagnosed in women. An estimated 12.7 million people were diagnosed with cancer across the world in 2008, and 7.6 million people died from the cancer during the same year [1]. Lung cancer, breast cancer, colorectal cancer and stomach cancer accounted for two-fifths of the total cases of cancers diagnosed worldwide [1]. More than 70% of all cancer deaths occurred in low- and middle-income countries. Deaths due to cancer are projected to continuously increase and it has been estimated that there will be 11.5 million deaths in the year 2030 [1] and 27 million new cancer cases and 17.5 million cancer deaths are projected to occur in the world by 2050 [2]. According to Canadian cancer statistics, issued by the Canadian Cancer Society, it is estimated that 186,400 new cases of cancer (excluding 81,300 non-melanoma skin cancers) and 75,700 deaths from cancer will occur in Canada in 2012 [1]. The lowest number of incidences and mortality rate is recorded in British Columbia. Both incidence and mortality rates are higher in Atlantic Canada and Quebec [3].

More than 30% of cancers are caused by modifiable behavioral and environmental risk factors, including tobacco and alcohol use, dietary factors, insufficient regular consumption of fruit and vegetable, overweight and obesity, physical inactivity, chronic infections from Helicobacter pylori, hepatitis B virus (HBV), hepatitis C virus (HCV) and some types of human papilloma virus (HPV), environmental and occupational risks including exposure to ionizing and non-ionizing radiation [4].

Conventional treatment of cancer includes interventions such as psychosocial support, surgery, radiotherapy and chemotherapy [4]. Currently, the most commonly use cancer chemotherapy includes mainly alkylating agents, antimetabolites, antitumor antibiotics, platinum analogs and natural anticancer agents. However, due to the increasing rate of mortality associated with cancer and adverse or toxic side effects of cancer chemotherapy and radiation therapy, discovery of new anticancer agents derived from nature, especially plants, is currently under investigation. Screening of medicinal plants as a source of anticancer agents was started in the 1950s, with the discovery and development of vinca alkaloids, vinblastine and vincristine and the isolation of the cytotoxic podophyllotoxins [5] (Figure 01). The cool temperate climate of North America supports the growth of an enormous number of plant species which are important sources of unique phytochemicals having anticancer properties (Table 01). In this chapter, selected medicinal plants grown in the cool climate of North America (mainly Canada and USA) are discussed. The major bioactive phytochemicals and their mechanisms of action are also reviewed.

Figure 1.

Some selected currently used phytochemical-based anticancer agents

Plant Family Parts used Major bioactive compounds Growing regions Ref
Achyranthes aspera
(Devil’s Horsewhip)
Amaranthaceae Leaf Triterpenoid saponins USA 14
Annona glabra
(Pond apple)
Annonaceae Leaf and fruit Acetogenins USA 15
Aralia nudicaulis
(Wild sarsaparilla)
Araliacea Whole plant Steroids, sarsasapogenin, smilagenin, sitosterol, stigmasterol, pollinastrenol, glycosides, saponins, sarsasaponin parillin, smilasaponin, smilacin, sarsaparilloside, and sitosterol glucoside Mainly Canada 16
Aster brachyactis
(Rayless aster)
Asteraceae Aerial parts Not known North America 17
Carduus nutans
(Nodding plumeless thistle)
Asteraceae Aerial parts Linalool derivatives, aliphatic acids, diacids, aromatic acids, and phenols North America 18, 19
Erythronium americanum
(Adder’s tongue)
Liliaceae Whole plant Alpha-methylenebutyrolactone North America 20, 21
Eupatorium cannabinum
Asteraceae Whole plant Sesquiterpene lactone, pyrrolizidine alkaloid, and flavonoid North America 20, 21,19, 22
Foeniculum vulgare
(Wild pepper fennel)
Apiaceae Seed α-pinene, anisic aldehyde, cineole, fecchone, limonene, and myrcene North America 23
Hydrastis canadensis
(Orange root)
Ranunculaceae Whole plant Isoquinoline alkaloids (hydrastine, berberine, berberastine, candaline), resin and lactone Canada, USA 20, 21
Hypericum perforatum
(St. John’s wort)
Clusiaceae Flower Hypericin and hyperforin USA, Canada (British Columbia) 24
Lactuca sativa
(Garden lettuce)
Asteraceae Leaf Sesquiterpene lactone USA, Canada 25
Lantana camara
(Wild sage)
Verbenaceae Whole plant Alkaloids (camerine, isocamerine, micranine, lantanine, lantadene), phenols, flavonoids, tannins, saponins, and phytosterols USA 26, 27, 28
Larrea tridentate
(Creosote bush)
Zygophyllaceae Whole plant Resins and lignans Southwestern USA 18, 29, 30
Linum usitatissimum
(Common Flax)
Linaceae Seed Enterodiol, enterolactone, lignans, and omega-3 fatty acids Canada, USA 31, 32
Olea europrae
Oleaceae Leaf and oil Oleuropein, hydroxytyrosol, hydroxytyrosol acetate, luteolin-7-O-glucoside, luteolin-4’-O-glucoside and luteolin, oleic acid and polyphenol USA 33, 34, 35, 36, 37
Panax quinquefolius
(North American Ginseng)
Araliaceae Root, Leaf Ginsenosides and saponins Eastern North America 20, 21
Plantago lanceolata
(Ribwort plantain)
Plantaginaceae Aerial parts Phenolics and flavonoids Canada, USA 38
Podophyllum peltatum
Berberidaceae Rhizome Podophyllotoxins Eastern North America 39
Polygonatum multiflorum
(Tuber fleece flower)
Polygonaceae Whole plant Saponin and flavonoid and vitamin A USA 20, 21, 40
Pyrus malus
Rosaceae Bark and fruit Quercetin, catechin, flavonoid, coumaric and gallic acids, phloridzin and procyanidin North America 21
Rhodiola rosea
(Golden root)
Crassulaceae Rhizome Monoterpene alcohols and their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives Eastern Canada 41, 42
Saponaria vaccaria
Caryophyllaceae Seed Flavonoids, cyclopeptides, and bisdesmosidic saponins Western Canada 43
Silybum marianum
(Milk thistle)
Asteraceae Dried fruit, seed Silymarin-polyphenoic flavolignans (silybin, isosilybin, silychristin, silydianin and taxifoline) Canada, USA 44, 45
Sonchus arvensis
(Perennial sow-thistle)
Asteraceae Whole plant Alkanes, n-alkenes, n-aldehydes and n-alcohols, shikimate metabolites, carotenoid-derived compounds, terpenoids, steroids, and phenols Canada 46, 47
Tanacetum vulgare
Asteraceae Aerial parts Monoterpenes, sesqueterpenes, and oxygenated sesqueterpenes Canada, USA 48
Taraxacum officinale
Asteraceae Root and leaf Sesquiterpene lactones, triterpenoids, sterols, tannins, alkaloids, inulin, caffeic acid, and flavonoids North America 49
Taxus brevifolia
(Pacific yew tree)
Taxaceae Bark Taxol (diterpene) Pacific Northwest 50
Thuja occidentalis
(White cedar)
Cupressaceae Whole plant Flavonoid, tannin, and volatile oil Northeastern USA,
Eastern Canada
13, 51
Xanthium strumarium
Asteraceae Fruit Sesquiterpene lactones (Xanthatin and Xanthinosin) Canada 17

Table 1.

Medicinal plants with potential anticancer properties grown in North America


2. Pathophysiology of cancer

Cancer is a population of abnormal cells which divide without control, with the ability to invade other tissues. Cancer and some of the other chronic diseases share common pathogenesis mechanisms, such as DNA damage, oxidative stress, and chronic inflammation [10]. It is understood that both environmental factors and chemical carcinogens play a key role in the initiation and progression of cancer. Among the major environmental factors are asbestos, polluted air near industrial emission sources, exposure to secondary tobacco smoke, indoor air pollution such as radon, drinking water containing arsenic, chlorination by-products, and other pollutants [11]. Chemicals with carcinogenic activity can be classified as DNA reactive (e.g.: nitrogen mustards, chlorambucil, epoxides, aliphatic halides, aromatic amines), epigenetic (e.g.: chlordane, pentachlorophenol, hormones, cyclosporin, purine analogs), dichlorodiphenyltrichloroethane, phenobarbital, minerals (e.g.: asbestos), metals (e.g.: arsenic, beryllium, cadmium) and unclassified carcinogens (e.g.: acrylamide, acrylonitrile, dioxane) [12]. DNA-reactive carcinogens act in the target cells of tissue(s) of their carcinogenicity to form DNA adducts that are the basis for neoplastic transformation [12]. Epigenetic carcinogens lack chemical reactivity and hence, do not form DNA adducts. These carcinogens are produced in the target cells of tissue(s) of their carcinogenicity. Effects of epigenetic carcinogens indirectly lead to neoplastic transformation or enhance the development of tumors from cryptogenically transformed cells [12].

Carcinogenesis is a multi-step process consisting of tumor initiation, promotion and progression [13]. Cancer initiation can be blocked by activating protective mechanisms, either in the extracellular environment or intracellular environment by modifying trans-membrane transport, modulating metabolism, blocking reactive oxygen and nitrogen species, maintaining DNA structure, modulating DNA metabolism and repair, and controlling gene expression [10]. Tumor promotion is the second stage of carcinogenesis and is followed by tumor progression. Both stages can be suppressed by inhibiting genotoxic effects, favoring antioxidant and anti-inflammatory activity, inhibiting proteases and cell proliferation, inducing cell differentiation, modulating apoptosis and signal transduction pathways and protecting intercellular communications [10]. In addition, tumor progression can also be inhibited by affecting the hormonal status and the immune system in various ways and by inhibiting tumor angiogenesis [10].


3. In vitro anticancer activity of phytochemicals and extracts of medicinal plants

Cultured cancer-derived cell lines with comparison to normal healthy cell lines are commonly used to assess the anticancer properties of isolated phytochemicals and extracts of medicinal plants (Table 2). The anticancer properties of ethanolic extract of leaves, pulp and seeds of, Annona glabra (L.), commonly known as pond apple, were shown, using human drug-sensitive leukemia (CEM) and its multidrug-resistant-derived (CEM/VLB) cell lines [52]. The most potent anticancer activity was shown in the seed extract of A. glabra [52]. Both dried rhizome hexane extract and dried fruit hexane extract, partitioned from total methanol extract, of Aralia nudicaulis (L.) caused death of cancer cell lines such as human colon cancer cell (WiDr), human leukemia cell (Molt) and human cervix cancer cell (HeLa) at a lower concentration, than that of required for the death of normal cells [53]. Eupatoriopicrin, a sesquiterpene lactone isolated from Eupatorium cannabinum (L.) (Bonesets), indicated anticancer properties on FIO 26 (fibrosarcoma) cells with an IC50=1.5 µg/ml [22]. Methanolic extracts of Hypericum perforatum (L.) (St. Johns wort) possessed strong antiproliferative activity in the human prostate cell line (PC-3) and the major constituents, hyperforin and hypericin, synergistically contributed to the reduction of the PC-3 cells proliferation [24]. Maslinic acid, (Figure 2(a)) a triterpene from Olea europaea (L.) (Olive), has shown to be significantly inhibitory in cell proliferation of the human colorectal adenocarcinoma cell line (HT29) in a dose dependent manner [33]. The major components in the extract were identified to be oleuropein, hydroxytyrosol, hydroxytyrosol acetate, luteolin-7-O-glucoside, luteolin-4’-O-glucoside and luteolin [34] (Figure 2). All these phytochemicals inhibited the proliferation of cancer and endothelial cells with IC50, at the low micromolar range [37]. Methanolic leaf extract of Plantago lanceolata (L.) (Ribwort plantain) inhibited the growth of three different cell lines; human renal adenocarcinoma (TK-10), the human breast adenocarcinoma (MCF-7) and the human melanoma (UACC-62) cell lines and the MCF-7 was totally inhibited [54]. Further, the ethanolic extract of P. lanceolata (L.), produced by maceration with ethanol : water, showed significant antiproliferative activity on cervix epithelioid carcinoma (HeLa), breast adenocarcinoma (MCF-7), colon adenocarcinoma (HT-29) and human fetal lung carcinoma (MRC-5) [38]. Several chemical constituents (Figure 3) from Silybum marianum (Milkthistle) have been isolated and their cytotoxic and anticancer potential has been investigated, in vitro, using both cancer and normal healthy cell lines. Silymarin, isolated from seeds of S. marianum, is a mixture of series of flavolignans, major constituents being: silybin A and B, (also known as silibinin), isosilybin A and B, silychristin, and silydianin [55, 56].

Figure 2.

Major bio-active compounds present in Olea europaea (a,b,c,d,e,f and g) and Plantago lanceolata (f and g)

Silybin possessed a dose-dependent growth inhibitory effect on parental ovarian cancer cells (OVCA 433), drug-resistant ovarian cancer cells (A2780 WT) and doxorubicin (DOX)-resistant breast cancer cells (MCF-7) [55]. Both L and D diastereoisomers of silybin inhibited A2780 WT cell growth at low IC50 reported with L-diastereoisomer [55]. Furthermore, silybin potentiated the effect of Cisplatin (CDDP, a platinum analog; cis-diamminedichloroplatinum [II]) in inhibiting A2780 WT and CDDP-resistant cell growth. Cisplatin is an inorganic metal complex which acts as an alkylating agent [57]. Similar results recorded with doxorubicin (DOX) on MCF-7 DOX-resistant cells when silybin associated with doxorubicin. Doxorubicin ((7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyace tyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione) is an anthracycline antibiotic isolated from Streptomyces peucetius var caesius [57]. The effect of silybin-CDDP and silybin-DOX combinations resulted in a synergistic action, as assessed by the Berembaum isobole method [55]. Silymarin demonstrated to have marked inhibition of cell proliferation with almost 50% inhibition in a time dependent manner on the human breast cancer cell line (MDA-MB 468), at 25 μg/mI concentration, after five days of treatment. Its potential anticancer activity was dose dependent and showed a complete inhibition of cancer cells at 50 and 75 μg/mI concentrations at the beginning of Day 2 of exposure [56]. Induction of apoptotic cell death of human prostate cancer (DU145) treated with silibinin is shown to be due to activation of caspase 9 and caspase 3 enzymes [58].


4. Evidence from animal studies for anticancer activity of North American medicinal plants

Anticancer and antiproliferative potential of some North American medicinal plants has also been studied in animal studies (Table 3). In vivo antitumor activities of Achyranthes aspera (L.) (Devil’s Horsewhip) on athymic mice, with are subcutaneous xenograft, harboring human pancreatic tumor were demonstrated, using the leaf extract. The leaf extract significantly reduced both tumor weight and volume in mice treated with leaf extract intraperitonealy [14]. Intravenous administration of 40 mg/kg body weight eupatoriopicrin, a sesquiterpene lactone present in E. cannabinum, significantly delayed the growth of tumor in Lewis lung tumour-bearing syngeneic C57B1 female mice [22]. A 70% inhibition of tumor growth in PC-3 cells, orthopedically implanted into the dorsal prostatic lobe in athymic nude mice, was observed, upon their receiving 15 mg/kg intraperitoneal H. perforatum methanolic extract [24]. Lantadene A is a pentacyclic triterpenoid, isolated from the weed, Lantana camara (L) [59]. Feeding of female Swiss albino mice (LACCA) with a dose of 50 mg/kg body weight of Lantadene A twice a week for 20 weeks, showed potential chemopreventive activity. This chemopreventive activity could be linked to the expression of transcriptional factors and a significant decrease in the mRNA expression of AP-1 and c-fos), NF-kB (p-65) and p53 was observed in Lantadene A treated mice skin tumors [59]. Silibinin decreased tumor multiplicity by 71% (P < 0.01) in wild type mice, but did not show any such considerable effect in iNOS-/- mice upon oral feeding of 742 mg/kg body weight silibinin for 5 days per week for 18 weeks [60]. Lesser effects of silibinin in iNOS-/- mice suggested that most of its chemopreventive and angiopreventive effects were through its inhibition of iNOS expression in lung tumors [60]. Treatment of a purified diet, containing 0.5% to 1.0% silibinin on a transgenic adenocarcinoma of are mouse prostate (TRAMP) model, decreased the weight of the tumor in both the prostate and seminal vesicle, when compared with control mice [61].

Figure 3.

Major bio-active flavonolignans present in Silybum marianum

Treatment of silibinin significantly decreased tumor angiogenesis and proliferation and also there was increased apoptosis in prostate tumor tissue samples in the TRAMP model [61]. The protective effect of silibinin was also demonstrated in mouse skin with tumors caused by acute and chronic UVB-exposure-caused mitogenic and survival signaling and associated biological responses [62]. Mice were treated with silibinin, either topically (9 mg in 200 ml acetone/mouse) or orally (1% of diet), and both administrations strongly inhibited UVB-induced skin tumorigenesis in a long-term study [62]. Thymine dimers are formed in DNA, immediately after UVB irradiation, and are considered as an early and important biomarker for UVB induced DNA damage [62]. A noticeable, 71% reduction (P < 0.001) of thymine positive cells was obtained in the mice treated with 1% (w/w) silibinin before the UVB exposure, compared with the UVB alone group [62]. Oral feeding of 200 mg/kg of silibinin for 5 days per week, for 33 days, significantly inhibited human non–small-cell lung cancer cells (NSCLC A549) tumor xenograft growth in nude mice, in a time-dependent manner [63]. This accounted for 58% (P = 0.003) reduction in tumor weight per mouse and intraperitoneal administration of 4 mg/kg doxorubicin, once a week for four weeks, showed 61% (P = 0.005) reduction in tumor weight. However, interestingly, in silibinin-doxorubicin combination, 76% (P = 0.002, versus control) decrease in tumor weight per mouse was observed, that which was significantly different from either treatment alone, showing enhanced efficacy [63].


5. Mode of action of selected phytochemicals of North American medicinal plants

Apoptosis (programmed cell death) is the principal mechanism through which unwanted or damaged cells are safely eliminated from the body. This programmed cell death is mediated via either an extrinsic apoptotic pathway or an intrinsic apoptotic pathway [65]. These two apoptosis signaling pathways differ in the origin of their apoptosis signal, but converge upon a common pathway [66].

The extrinsic pathway is initiated by the stimulation of the cell surface ‘death receptor’ due to the binding of death ligand and the intrinsic pathway is also known as the mitochondrial pathway in which an intracellular apoptotic signal initiates the process [68]. Various natural extracts, obtained from medicinal plants grown in North America, have been found to induce apoptosis pathways at different levels (Figure 4 and Table 04). Leaf extract of Achyranthes aspera activated caspase-3 and induced caspase-3 mRNA in tumor cells. It also decreased Akt-1 transcription, as well its phosphorylation. Suppression of pAkt-1 and a corresponding activation of caspase 3 by the leaf extract, induced apoptosis of tumor cells [14]. It was also found that maslinic acid, isolated from O. europaea, inhibited considerably the expression of Bcl-2 (B-cell lymphoma 2), whilst increasing that of Bax. Maslinic acid stimulated the release of mitochondrial cytochrome-c and activated caspase-9 and caspase-3 [33]. These results showed the activation of the mitochondrial apoptotic pathway, in response to the treatment of HT29 colon-cancer cells with maslinic acid. The major flavonoid present in P. lanceolata, luteolin-7-O-β-glucoside, as well as aglycon luteolin, acted as potent poisons for DNA topoisomerase I on cancer cell lines [54]. Silibinin (major bioactive component from S. marianum) markedly activated the DNA-PK-p53 pathway for apoptosis, in response to UVB-induced DNA damage [69]. DNA-PK pull-down assay showed that silibinin pre-treatment strongly increased binding of DNA protein kinase with p53 [69].

Plant Extraction solvent and concentration Type of cancer cell line IC50 or growth reduction Key findings Ref.
Annona glabra
(Pond apple)
Ethanolic extract of lyophilized plant material in powder form Human drug-sensitive leukemia (CEM) and its multidrug-resistant-derived (CEM/VLB) cell lines Leaf-1.00 (CEM/VLB) Pulp-0.65 (CEM/VLB), Seed-0.10 (CEM/VLB) and Leaf-0.30 (CEM), Pulp-0.35 (CEM), Seed-0.07 (CEM) µg/ml IC50 values were significantly lower than Adriamycin (Doxorubicin) (CEM=0.13 μg/ml and CEM/VLB=13.4 μg/ml) indicates its potential for cancer drug discovery programs 52
Aralia nudicaulis
(Wild sarsaparilla)
Methanol extracts of rhizome, stem, leaf and fruit were further partitioned with hexane, ethyl acetate, butanol and water WiDr (colon), Molt (leukemia), HeLa (cervix) Hexane rhizome extract 30.1 (WiDr), 7.0 (Molt), 33.33 (HeLa) µg/ml The concentrations of Rhizome hexane and Fruit hexane required for normal cell death was significantly higher than those required for the cancer cells 53
Eupatorium cannabinum
Eupatoriopicrin concentrations of 0.1 - 50 µg/ml in 96% ethanol FIO 26 (Fibrosarcoma) 1.5 µg/ml Possess significant anticancer activity 22
Foeniculum vulgare
(Wild pepper fennel)
Not specified Breast (MCF-7), liver (HepG2) - Remarkable anticancer potential 23
Hypericum perforatum
(St. John’s wort)
Methanolic extract Prostate (PC-3) 0.42 mg/ml Extract components synergistically contribute to the reduction of the PC-3 cells proliferation 24
(Common flax)
Ethanol extract Breast (MCF-7, MDA-MB-231) Growth reduction of 15.8% in MCF-7 and 11.4% in MDA-MB-231 Significantly reduced cell growth and induced apoptotic cell death 31
Olea europrae
maslinic acid 0–100 µg/mL Colon (HT29) 28.8 µg/ml Cell proliferation inhibition in a dose-dependent manner and causes apoptotic death 33
Aqueous extract and methanol artificial mixture Breast (MCF-7), Human urinary bladder (T-24), Bovine brain (BBCE) 72 (MCF-7), 100 (T-24), and 62 (BBCE) for aq. 565 (MCF-7), 135 (T-24), and 42 (BBCE) for methanol µg/ml Antiproliferative activity of the extracts should mainly be attributed to its identified phytochemicals 34
Plantago lanceolata
(Ribwort plantain)
Methanolic extract Renal (TK-10), breast (MCF-7), melanoma (UACC-62) "/>250 (TK-10), 47.2 (MCF-7), 50.6 (UACC-62) μg/mI Growth of MCF-7 was totally inhibited 54
Extracted by maceration with ethanol/water during 72 hr at room temperature cervix epitheloid (HeLa),breast (MCF-7), colon (HT-29), fetal lung (MRC-5) 172.3 (HeLa), 142.8 (MCF-7), 405.5 (HT-29), 551.7 (MRC-5) µg/ml Showed significant antiproliferative activity 38
Rhodiola rosea
(Golden root)
Not specified Urinary bladder (RT4, UMUC-3, T24, 5637, J82) 264 (RT4),100 (UMUC-3), 71 (T24), 151 (5637), 165 (J82) μg/ml Selectively inhibit the growth of cancer cell lines with minimal effect on nonmalignant cells 41
Saponaria vaccaria
70% Methanol extract colon (WiDr), breast (MDA-MB-231), lung (NCI-417), prostate (PC-3), nontumorigenic fibroblast BJ (CRL-2522) 3.8-9.4 (WiDr), 11.4-19.6 (MDA-MB-231), 12.6-18.4 (NCI-417) mg/mI Dose-dependent growth inhibitory and selective apoptosis-inducing activity. Strong in a breast and a prostate cancer cell lines 43
Silybum marianum
silybin, a flavonoid Doxorubucin resistant breast (MCF-7), Parental ovarian (OVCA 433), Drug-resistant ovarian (A2780) 4.8-24 μM (MCF-7), 14 & 20 μM - L & D diastereoisomers respectively (A2780)
25 μg/mI
Dose-dependent growth inhibitory effect on all three cell lines 55
Silymarin at a dosages of 10- 75 μg/mI in ethanol Breast (MDA-MB 468) -
Inhibits the cell proliferation in a dose- and time dependent manner 56
Silibinin in DMSO Prostate (DU145) - Strongly inhibited activation of Stat3 and causes caspase activation and apoptotic death 58
Isosilybin A and B Prostate (LNCaP, 22Rv1)
Prostate (DU 145)
Iso A:32 μM (DU 145)
Iso B:20 μM (DU 145)
Anti-prostate cancer activity mediated via cell cycle arrest and apoptosis induction 69
Taraxacum officinale
Water (lyophilized or reconstituted) Acute T-cell leukemia (Jurkat clone E6-1), dominant-negative FADD Jurkat cells (clone I 2.1) - Effectively and selectively induced apoptosis in human leukemia cell lines in a dose and time dependent manner 49

Table 2.

Anti-cancer properties of phytochemicals and extracts of medicinal plants revealed from in vitro studies using cancer cell lines

Plant Preparation Animal model used Dosage Key findings Ref.
Achyranthes aspera
(Devil’s Horsewhip)
5% suspension in hexane followed by extraction in acetone overnight and residue was dissolved in methanol Athymic nude mice 50, 100 and 200 mg/kg extract in 1 ml PBS administered IP The tumor weight and volume was significantly reduced in the mice treated for 36 days with 50 mg/kg. In one treated mouse tumor completely disappeared 14
Eupatorium cannabinum
Eupatoriopicrin, a sesquiterpene lactone Syngeneic C57B1 female mice i.v. injection of 20 or 40 mg/kg Significantly stronger growth delay of both lung tumours and fibrosarcoma 22
Hypericum perforatum
(Orange root)
Methanolic extract Human prostatic carcinoma cell line orthotopically implanted athymic male nude mice ip with a dose of 15 mg/kg dissolved in 1% DMSO Inhibited tumor growth by 70% with no observed side effects 24
Lantana camara
(Wild sage)
Lantadene A, pentacyclic triterpenoid Female Swiss albino mice (LACCA) 50 mg/kg body weight twice a week for 20 weeks Activity could be linked to the expression of transcriptional factors 59
Silybum marianum
Silibinin Lung - Male B6/129-Nos2tm1Lau (iNOS-/-) and B6/129PF2 WT mice 742 mg/kg body weight for 5 d/wk for 18 weeks Significantly decreases urethane-induced tumor number and size in WT mice. Decreased tumor multiplicity in WT mice, but not in iNOS-/- mice 60
Silibinin Prostate - A transgenic adenocarcinoma of mouse prostate (TRAMP) model Purified diet containing 0% and 1%
(w/w) silibinin until
Decreased the weight of tumor + prostate + seminal vesicle. Significantly decreased tumor angiogenesis and proliferation and increased apoptosis also. 61
Topically applied silibinin in acetone or oral feeding of silibinin Skin – mouse 9 mg in 200 ml acetone/mouse or 1% in diet silibinin (both topical and oral) strongly inhibited UVB-induced skin tumorigenesis in long-term study 62
Skin - SKH-1 hairless mouse 1% (w/w) silibinin in diet for 2 weeks Strong suppression of UVB-induced damage by dietary feeding of silibinin 63
Silibinin Athymic (BALB/c,nu/nu) male nude mice 200 mg/kg body weight, 5 d/wk for 33 days
Significantly inhibits human NSCLC A549 tumor xenograft growth in a time dependent manner 64

Table 3.

Anti-cancer properties of medicinal plants revealed from in vivo studies using experimental animals

Figure 4.

Schematic representation of current knowledge of mode of action of some selected anticancer phytochemicals in North America (in a hypothetical cancer cell).

Akt (Protein kinase B); Bcl-2 (Protein kinase B); Bax (Bcl-2–associated X protein); Topo-1 (Topoisomerase 1); p53 (tumor protein 53); Ser15 (Serine 15); NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells); AR (Androgen Receptor)

  1. Methanolic leaf extract of Achyranthes aspera (MLAa) induces caspase -3 mRNA and suppress expression of the kinase Akt-1. Apoptosis is induced by activation of caspase-3 and inhibiting Akt-phosphorylation.

  2. The mechanism of Maslinic acid (MSA) (isolated from Olea europaea) is regulated via Bcl-2 inhibition and Bax induction, producing mitochondrial disruption, cytochrome-c release, leading finally to the activation of caspases 9 and caspase 3.

  3. Luteolin-7-O-β-glucoside and its aglycon, luteolin (major bio-active constituents of Plantago lanceolata) showed DNA topoisomerase I poison activities and Topoisomerase mediated DNA damage might be the possible mechanism which induce apoptosis.

  4. Silibinin (SBN) (extracted from Silybum marianum) pretreatment enhance DNA-PK (DNA Protein kinase) associated kinase activity as well as the physical interaction of p53 with DNA-PK and it preferentially activates the DNA-PK-p53 pathway for apoptosis.

  5. SBN inhibits active Stat3 phosphorylation, and causes caspase activation and apoptosis.

  6. Isosilybin A (ISBN) (extracted from Silybum marianum) activates apoptotic machinery in human prostate cancer cells via targeting Akt–NF-kB–AR axis.

  7. ISBN increases p53 protein levels.

Plant Mode of action References
Achyranthes aspera
(Devil’s Horsewhip)
Significantly induced caspase-3 mRNA and suppressed expression of the pro survival kinase Akt-1. Apoptosis was induced by activation of caspase-3 and inhibiting Akt phosphorylation. 14
Olea europaea
Activation of the mitochondrial apoptotic pathway
Significant block of G1 to S phase transition manifested by the increase of cell number in G0/G1 phase
Plantago lanceolata
(Ribwort plantain)
The topoisomerase-mediated DNA damage seems to be a candidate mechanism, by which some flavonoids may exert their cytotoxic potential 54
Silybum marianum
Induces G1 arrest in cell cycle progression
Up-regulates DNA-protein kinase-dependent p53 activation to enhance UVB-induced apoptosis
Activates apoptotic machinery in human prostate cancer cells via targeting Akt–NF-kB–AR axis
Inhibits active Stat3 phosphorylation, and causes caspase activation
Increases total p53 levels
Podophyllum peltatum
Inhibition of microtubule assembly 70

Table 4.

Mode of action of anticancer activity of phytochemicals present in selected North American medicinal plants


6. Conclusion

Currently, natural products, especially plant secondary metabolites such as isoprenoids, phenolics and alkaloids, have been demonstrated to be the leading providers of novel anticancer agents. Thiese important groups of phytochemicals represent a vast majority of chemical groups, including alkaloids, flavonoids, flavonols, flavanols, terpenes and terpenoids, phenols, flavonolignans and steroids. Potential anticancer properties of these phytochemicals have been shown by both cell culture (in vitro methods) and animal (in vivo methods) studies. However, in vitro and in vivo findings should be strengthened by valid human clinical trial data before introducing to the medicine cabinet as natural therapeutics or drugs.



CEM, Human drug-sensitive leukemia cells; CEM/VLB, Human multidrug-resistant-derived leukemia cells; Jurkat clone E6-1, Acute T-cell leukemia cells; WiDr and HT29, Human colon cancer cells; Molt, Human leukemia cancer cell; FIO 26, Human fibrosarcoma cells; MCF-7 and MDA-MB-231, Human breast cancer cells; HepG2, Human hepatocarcinoma cells; LNCaP, 22Rv1, PC-3 and DU145, Human prostate cancer cells; RT4, UMUC-3, T24, 5637 and J82, Human urinary bladder cancer cells; BBCE, Bovine brain capillary endothelial cells, TK-10, Human renal cancer cells; UACC-62, Human melanoma cells; HeLa, Human cervical epithelioid cells; MRC-5, Fetal lung cancer cells; NCI-417, Human lung cancer cells; CRL-2522, Human nontumorigenic fibroblast cells; OVCA 433, Parental ovarian cancer cells; A2780, Drug-resistant ovarian cancer cells.


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Written By

Wasundara Fernando and H. P. Vasantha Rupasinghe

Submitted: 23 October 2012 Published: 19 June 2013