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    Herbal Treatment Strategies for Breast Cancer
       
     
    Umber Shahid*1
     
    1University of Texas, School of Public Health at Houston, TX, USA
     
    *Corresponding author: Umber Shahid, University of Texas, School of Public Health at Houston, TX, USA; Tel: 281-730-2380; Email: Umber.shahid@uth.tmc.edu
     
    Abbreviations: BC: Breast Cancer; CAM: Complementary and Alternative Medicines; SEER: Surveillance, Epidemiology, and End Results; HRT: Hormonal Replacement Therapy; TCM: Traditional Chinese Medicine; CHP: Chinese Herbal Products; MCF: Michigan Cancer Foundation
     
    Abstract
     
    Complementary and alternative medicine (CAM) use is common amongst cancer patients particularly breast cancer patients are the most likely users. Numerous studies support that herbal medicines are amongst the most commonly used group of treatments among CAM. Herbal remedies are assumed by the general public to be safe, cause less complications and are less likely to cause dependency. The foremost reasons of CAM (including herbal remedy) popularity among breast cancer patients include improving quality of life, supporting conventional cancer treatment, preventing recurrence and eventually to prolong survival.

    However there remains limited scientific evidence on the efficacy and safety of natural therapies including herbal remedies. The potential for interactions of herbal with conventional medications, consumption of high dose with consequent adverse effect and the limited, insufficient data concerning the possible hazards of herbal consumption, pose serious public health issues. Vigorous clinical trials are required to establish the efficacy or presence of any adverse effects of such preparations.
     
    1. Introduction
    1.1 Breast Cancer
     
    Breast cancer (BC) continues to be the most frequently occurring cancer in women around the world. The increased incidence, mortality, economic costs, is a burden shared among women globally [1]. BC continues to be a major public health problem in developed as well as developing countries [2]. Unfortunately, in spite of improved diagnostic skills and breakthrough in effective treatment, BC continues to be the leading cause of cancer deaths among women worldwide, with approximately 375,000 deaths in the year 2000 [1,2]. Moreover it is also accountable for greater than one million of the estimated 10 million diagnosed cancers worldwide each year in both sexes [3]. One in ten of all new cancers diagnosed worldwide each year are a cancer of the female breast. The burden differs between countries and regions showing variations in incidence, mortality and survival rates [1,5]. The age-standardized incidence of breast cancer is generally lower in developing countries than in developed countries (23.1 versus 63.2 per 100,000 women) however the incidence rates vary widely between and within countries [4,6]. Over the past several decades, the risk of breast cancer in developed countries has increased by one to two percent annually [7].

    Researcher believe that these variations are related to multiple factors such as health habits, socio-economic status, lifestyle changes (for example, later childbearing and dietary changes), exposure to radiation or family history, associated changes in menstrual patterns in addition to access and availability of care, early detection, and access to the current knowledge regarding BC [5,8]. Age is the single most important risk factor for breast cancer. Compared with women in their twenties, women are 10 times as likely to develop breast cancer in their thirties, 40 times as likely in their forties, 60 times as likely in their fifties, and 90 times as likely after age 60 [7].

    Prognosis is heavily dependent on stage of disease at presentation, however based on the Surveillance, Epidemiology, and End Results (SEER) registries in the US 5-year survival for localized cases in 1994 was about 97% but was only about 25% for cases with metastatic disease [3]. In developing countries, the differences in survival by stage at diagnosis are also very marked.

    Female breast cancer incidence rates vary nearly five-fold across the regions of the world. In 2008, rates ranged from around 20 per 100,000 in Eastern and Middle Africa to 90 per 100,000 in Western Europe [9]. The countries with the highest incidence rates in 2008 were Belgium and Denmark (109 and 101 per 100,000, respectively) while the incidence rate of UK women was high at 11th highest out of 184 countries worldwide [9]. Taking example of the US, breast cancer is the second most common cause of cancer death among women ages 40 to 49 years with an estimated 40,410 breast cancer deaths in US in year 2005 [10]. Breast cancer death rates for women in the US are higher than those for any other cancers, besides lung cancer. The chances that breast cancer will be responsible for a woman's death is about 1 in 36 (about 3%) [3]. However based on the stage of diagnosis, breast cancer is treated with a multidisciplinary approach involving surgery, radiation and medical oncology including chemotherapy or hormonal therapy. Doctors today most commonly employ a combination of local treatments that remove or destroy cancer in the breast (such as surgery and radiation) and systemic treatments that destroy or control cancer cells throughout the body (such as chemotherapy and hormonal therapy).
     
    1.2 Complementary and alternative medicines (CAM)
     
    Several new studies have discovered that most patients on cancer therapy are concurrently self-medicating with one or several complementary and alternative medicines (CAM) [11]. CAM is the term used for medical products and practices that are not part of standard medical care. Standard care is practiced by medical doctors and allied health professionals, such as nurses and physical therapists. "Complementary medicine" refers to treatments that are used with standard treatment such as is using acupuncture to help with side effects of cancer treatment. "Alternative medicine" refers to treatments that are used instead of standard treatment for example using a special diet to treat cancer instead of a method that a cancer specialist/doctor suggests. Standard treatments are based on scientific evidence from research studies, while CAM is based on claims made by CAM treatment providers. The consequence of most of these agents on the effectiveness and toxicity of regular anticancer treatment have not been considered, which poses a great threat to patients [11].

    CAM is often associated with different terms such as "natural, holistic, home remedy or Eastern medicine" and is divided into five broad categories [12]. i) Mind-Body Medicines including hypnosis, yoga,
    ii) Biologically based practices such as herbs, vitamins, special diets
    iii) Manipulative or body based practices of massage, chiropractic care
    iv) Energy medicine
    v) Whole medical system

    The prevalence of CAM (including herbal treatment) use is estimated at 25% among residents of the United Kingdom [13,14] 50% among German, French [14], and Australian [15] populations, and 42% to 69% among residents of the United States [16,17]. CAM is a major growth industry in Europe [13], and that trend is now mirrored in the United States, where typical characteristic of a CAM user is described as wealthy, white Americans with good education, commonly between the ages of 30 to 50 years, and residing in the northeastern or western regions of the country [13,18].

    A study by Janette et al. (2013) supported above finding of CAM utilization by a large proportion of cancer patients (mean 36%, range up to 80%) [19] And among cancer patients, breast cancer patients remain as the most likely users [20]. Furthermore, among the CAM users almost half of the patients (50%) use herbal supplements or anti-oxidants at some phase during their cancer treatment. The maximum use of CAM among people with cancer is in women [21], particularly with breast cancer, who are of younger age, with higher levels of education, have more advanced disease and are of Asian ancestry [19-21]. Furthermore, the majority of patients do not notify their doctors about their CAM utilization [19,22].

    A summary of 26 surveys across 13 countries concluded that the prevalence of CAM use by cancer patients overall was 31.4% (range, 7% to 64%). In the United States between 1990 and 1997, the prevalence of CAM use increased from 33.8% to 42.1%, and the number of visits to CAM practitioners increased from 427 million to 629 million visits with an estimated out-of-pocket expenditure of $34.4 billion in year 1997 [13].
     
    2. Herbal Treatment and Breast Cancer
     
    Among Complementary and alternative medicines, herbal medicine is the most commonly used group of treatment. Herbal treatment is the oldest used system of medicine in the world with more than 2000 years history [23]. Other names used for herbal therapy are phyto-medicine, phyto-therapy or botanical medicine. It is a medicine made exclusively from plants such as roots, bark, flowers, seeds, fruits, leaves, or branches and is used in all societies and common to numerous cultures including Asia, Africa, Europe and America. There are various types of herbal medicine that spring from different cultures around the world however they vary in the way they are prepared and in their treatment approaches [24].

    Certain herbs defend the body from malignancy by augmenting detoxification or cleaning role of the body. Some biological response modifiers, derivatives of herbs, are recognized to hinder the growth of cancer by modifying the activity of precise hormones and enzymes, while other herbs diminish lethal side effects and complications of chemotherapy and radiotherapy [25]. Moreover, phytoconstituents resulting from the herbs such as Vinca rosea, Taxus species, Allium sativum, Aloe vera, Angelica sinensis, Astragals membranaceus, Glycine max, Glycyrrhiza glabra, Hordeum vulgare, Hydrocotyle asiatica, Medicago sativa, Morinda citrifolia, Panax pseudoginseng, Saussurea lappa, Taxus wallichiana, Tinospora cordifolia, Viscum album, Withania somnifera, Zingiber officinale etc. have been used in numerous preparations to improve function of the body’s immune cells that stimulates production of cytokines including interleukin, interferon, tumor necrosis factor as well as colony stimulating factor. These preparations assist the body to battle cancer more efficiently and also decrease the harmful side effects of chemotherapy and radiotherapy [25].

    Herbal formulae have been prescribed to adults, children, and elderly, as well as pregnant and lactating mothers. Compared to Eastern part of the world where herbal treatments play a central role, they are not as popular in the United States. Such treatments form a complete medical system that is integrated in modern hospitals and clinics throughout most of Asia. Literature documents the current popularity of natural alternatives to conventional medical treatments, especially among patients with chronic life-threatening diseases such as cancer [26].

    Most cancer patients combine CAM (herbal remedies) with conventional therapy in the hope of boosting the effect of conventional medicine [22,27]. A study of women being treated for early stage breast cancer showed that 10.6% had been using one or more CAM at the time of diagnosis, while an additional 28.1%began using CAM (including herbal remedies) after surgery [11]. Similarly a multinational survey found that 35.9% of cancer patients were either past or present users of complementary and alternative medicine. Herbal medicines were by far the most commonly used group of treatments, escalating in use from 5.3% before the diagnosis of cancer to 13.9% after the diagnosis of cancer [24].

    Generally, herbal products are utilized for two reasons, first, to lessen symptoms of disease and second to prevent sickness. Examples include palliative use of St. John’s Wort (Hypericum perforatum) for relief of acute depression, the use of Ginkgo biloba for enhancement in perception/understanding and the use of Echinacea for improving cold symptoms [28]. In the second circumstance, herbal supplements are taken especially in the anticipation of averting disease or modifying the effects of threat for certain illnesses. Such as intake of green tea and other ?avonoid rich botanicals to yield benefit of the natural antioxidants in them and the consumption of garlic because of the high organo-sulfur compounds that have been experimentally proven to prevent cancer in animals [28].

    In the domain of cancer prevention, herbs may performance through numerous mechanisms to shield the body. Initiation of phase I and phase II metabolic enzymes by herbal supplements is quite typical and maybe liable for some of this action [28]. These phase I and II enzymes provide major protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens through initiation of their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases [29]. Taking example of garlic, its intake and supplement use is prevalent in both, Eastern and Western cultures [30]. Garlic along with numerous other organo-sulfur compounds derived from garlic demonstrate robust chemo-preventive action against experimentally induced cancers of the mammary gland as well as esophagus, stomach, colon, liver and lungs [28]. Initiation of phase I and phase II enzymes, nonetheless, can result in a likely significant side effect of herbal products. Such as St. John’s Wort that is extensively utilized, has been shown to encourage the CYP3A family of activation enzymes, through which half of current medications are also metabolized, hence offering the likelihood of herb-drug interactions [28].
     
    3. Common Herbs used Globally in Treatment for Breast Cancer
     
    3.1 Echinacea
     
    Echinacea, a member of the family Asteraceae is a wild herb that grows primarily in the Great Plains and eastern regions of North America. It is also cultivated in Europe. Three different species of the plant are used in herbal remedies namely Echinacea purpurea, Echinacea angustifolia, and Echinacea pallida however Echinacea purpurea is most frequently used for research and treatment. Other common names associated with Echinacea are purple coneflower, Kansas snakeroot and black Sampson [31]. Studies have found that Echinacea purpurea increases the amount of natural killer cells in the experimental mice and suggested that E. purpurea could be a possible treatment for anti-tumor therapy in the future [31]. Winston et al supported the ability of Echinacea, which is rich in flavonoids that act as an immune-stimulant, by promoting the activity of lymphocytes, increasing phagocytosis by macrophages and the activity of natural killer cells and inducing interferon production [32] at the same time reduces the adverse effect of radiotherapy and chemotherapy. It has also been used in an effort to prolong survival time in patients with advanced stage cancer. Commercial preparations of echinacea juice have been shown to increase cytokine production by macrophages [33]. A series of in-vitro 10 studies have demonstrated that stimulates various immune cells including Echinacea purpurea macrophages, polymorphnuclear granulocytes and natural killer cells. Effects on T-cell and B-cell 7 activation and proliferation are less clear. Several constituents of Echinacea are considered to play a role in its effects on the immune system [34].
     
    3.2 Licorice
     
    Glycyrrhizin is a chief constituent of licorice root and is a sweet tasting triterpenoid saponin. Licorice is a perennial plant that grows in southern Europe, Asia, and the Mediterranean. The dried roots and underground stems of the plant are used in herbal remedies. Glycyrrhizin along with its aglycone and glycyrrhetinic acid have also been stated to encourage activity of interferon, supplement the movement of natural killer cells and modulate the growth response of lymphocytes through augmentation of IL-2 production [32,35-37]. Experimental studies have recognized number of substances in licorice that may help avert DNA mutations, reduce tumor development, or even destroy cancer cells including breast cancer, prostate cancer, and leukemia cells. In studies with mice, glycyrrhizin and glycyrrhizic acid decreased the initiation of colon, liver, uterine, and breast cancers [32]. Licorice root also contains powerful antioxidants, as well as certain phyto-estrogens that can perform some of the functions of the body's natural estrogens. Research has demonstrated that this estrogenic effects of licorice components help to slow the progression of breast cancer [38,39]. Other studies have further shown that the bioactive compounds of licorice may be chemopreventive in other cancers, including prostate cancer.
     
    3.3 Cat’s Claw
     
    Two species of cat's claw, Uncaria guianesis and U. tomentosa, found in northern regions of South America and belonging to madder family (Rubiaceae), have also gained much attention particularly in the West because of their immune-stimulant properties as they contain a rich source of phytochemicals with more than 30 known constituents including at least 17 alkaloids, along with glycosides, tannins, flavonoids, sterol fractions, and other compounds found in the root and stalk bark [32,40].

    This indigenous herb has led scientists in the US and other countries to closely examine its effects in the body. Their findings suggest that this botanical agent exerts powerful anti-inflammatory and antioxidant effects that support DNA repair, joint health, immune function, and normal cell division [41].

    Cat’s claw extract inhibits the production of tumor necrosis factor-alpha, an inflammatory messenger that sets the stage for both acute and chronic inflammation. Likewise it inhibits the activation of nuclear factor-kappa beta, an inflammatory “switch” that is associated with cancer and other deadly diseases [42]. Extracts and fractions of cat's claw have been reported to stimulate T cells, macrophages, and other components of the immune system [32] as well as have antimutagenic and antiinflammatory properties [32,40].
     
    3.4 Garlic
     
    (Allium sativum) intake of garlic as a therapeutic agent has been practiced since past several decades to treat numerous illnesses. It encompasses hundred or more biologically beneficial secondary metabolites, such as alliin, alliinase, allicin etc. Garlic oil comprises of an amino acid identified as Alliin, which is transformed to Allicin once its bulbs are crushed. Allicin is a predecessor to numerous sulphur comprising compounds that are accountable for the taste, aroma as well as its pharmacological properties. Ajoene, another sulphur holding compound, present in garlic oil, impedes mutagenesis while selenium act as a cellular antioxidant. Researches have also discovered the existence of bioflavonoids cyanidin and quercetin, which are liable for antioxidant characteristic of garlic [43-45]. The antitumor property of Garlic is attributed to its high level of a wide-ranging diversity of organic sulfides and polysulfide’s. It is known to augment action of the immune system by activating lymphocytes and macrophages to kill cancer cells. It is also identified to interrupt the metabolism of tumor cells [32].

    Moreover, garlic prevents creation as well as development of cancer by increasing action of the natural killer cells and the macrophages. Researchers have discovered that garlic enhances amount of the suppressor T cells and turns the lymphocytes further cytotoxic to tumor cells. It also restrains metastases by averting union or adhesion of the circulating tumor cells to the blood vessels. The ripened extract of garlic shields DNA from the harmful influence of carcinogens, surges activity of detoxifying enzymes, hustles up elimination of chemical carcinogens and boost body’s immune system. Further, (mature garlic extract) it is known to prevent development of several tumors including those of the breast, lungs, stomach, colon and bladder. An investigation done at the National Medical Centre and Hospital in Japan has shown that the Garlic extract lessens complications of radiotherapy and chemotherapy as well [25,46,47].
     
    3.5 Flaxseed
     
    (Linum usitatissimum) contains a rich supply of lignans. By bacterial fermentation these plant lignans are transformed into mammalian lignans (enterolactone and enterodiol) in the colon and they can thereafter behave as estrogens [32,48]. Mammalian lignans appear to be anti-carcinogenic because lignan metabolites hold a structural resemblance to estrogens and can attach to estrogen receptors to hinder the development of estrogen-stimulated breast cancer. In women with breast cancer urinary excretion of lignans is reduced, while the intake of flaxseed powder enhances urinary concentration of lignans by many folds [32,49-52].

    Experimental studies of flaxseed diet on a mouse model, have demonstrated dose dependent inhibition of breast tumor growth [53]. Human trials also confirmed similar beneficial effects. A double-blinded, randomized controlled trial of dietary flaxseed demonstrated dramatic protection with a significant apoptosis (tumor cell death) and reduced cell proliferation [54]. Likewise women eating more flaxseeds were found to have a 42% reduced risk of death from postmenopausal breast cancer and a dramatic (40 percent) reduction in all causes of death [55]. Another interesting study on flax followed women for up to 10 years and found a 51% reduced risk of all-cause mortality and a 71% reduced risk of breast cancer mortality
     
    3.6 Turmeric
     
    (Curcuma longa) imparts a rich yellow color to food. The root and rootstock, or rhizome, of the plant contains curcumin, which is considered to be the active ingredient. Its anti-mutagenic action as well as cancer inhibition activity is attributed to its phenolic constituents. Turmeric has been shown to curb the progress of breast, lung, stomach and skin malignancies [32,56]. Its antioxidant curcumin (a diferuloylmethane), has been shown to be a successful anti-inflammatory agent in humans and slows down the development of cancer by averting the production of toxic eicosanoid such as PGE-2 [32]. This anticancer outcome has been established in all the phases of tumor growth, i.e. initiation, promotion and progression. Studies have revealed that Curcuma longa inhibits production of nitrosamine that enhances natural antioxidant functions of the body. Curcuma longa increases levels of glutathione and other non-protein sulphahydryls and acts directly on several enzymes [25,57]. Numerous research also advocates that curcumin hampers the initiation of cancer as well as encourages its deterioration [25,32]. Laboratory studies support that curcumin interferes with several important molecular pathways involved in cancer development, growth, and spread while researchers report that curcumin inhibits the formation of cancer causing enzymes in rodents [58].
     
    3.7 Burdock
     
    (Arctium lappa) is a root that is found in Europe and Asia. It has many medicinal qualities and has been used in many herbal remedies. The root is sweet to taste and has a gummy consistency. Traditionally, burdock has been used as a remedy for measles, arthritis, tonsillitis, while in modern times; burdock is used in oncology as well as in many other serious health problems. It comprises of some powerful anticancer features that averts mutations in the oncogenes. It has been used in the management of breast cancer, ovary, bladder, malignant melanoma, lymphoma and cancers of the pancreas. Studies document that it decreases the size of tumor, ease the pain and prolongs the survival phase [25].

    During the development of tumors, very large amounts of nutrients (oxygen and nutrients) are required to sustain the rapid proliferation of tumor cells. However, tumor cells can still survive under extreme conditions such as low oxygen and low carbohydrate availability due to their relatively high tolerance to hostile environment. Arctigenin, an active compound found in the seeds of burdock, has the ability to eradicate nutrient-deprived cancer cells [59]. In addition flavoniod-type antioxidants and some other active polyphenol antioxidants found in the root of burdock may account for the suppressive effects on cancer metastasis [60]. It has been shown that extracts of the root protect cells from toxic substances and lower the mutations of cells.

    Tannin, a phenolic compound, is one of the most common active compounds found in the root of burdock. It induces macrophage responses, inhibits tumor growth and possesses immuno-modulatory properties [61].
     
    3.8 Carotenoids
     
    Carotenoids are the pigments found in green, leafy herbs, rose hips, and the herbs used as coloring agents, such as paprika, saffron, and annatto. Epidemiologically, vegetable and fruit consumption has constantly been associated with a reduced incidence of a variety of cancers [62] and dietary carotenoid intake from these sources has similarly been correlated with a reduced cancer risk [63]. Major carotenoids with antioxidant activity that have been extensively evaluated with regard to their cancer chemopreventive ability include ß-carotenes, ß-cryptoxanthin, lycopene, lutein and zeaxanthin. However, studies tend to agree that overall intake of carotenoids is more protective than a high intake of a single carotenoid [64].

    The carotenoid pigments are powerful antioxidants and exhibits several biological activities, including the scavenging of free radicals, shielding against oxidative injury to cells, enhancement of gap junctions, immunomodulation and regulation of the enzyme activity involved in carcinogenesis as well as stimulate the immune function of the body [65]. Freudenheim et al. have shown that the intake of carotenoid-rich foods, specifically vegetables, as well as lutein and zeaxanthin, is significantly associated with a lower risk of developing premenopausal breast cancer [66]. People who have elevated serum levels of carotenoids demonstrate less risk of both cancer and heart diseases [32,67].
     
    3.9 Green tea
     
    Polyphenolics in green tea (Camellia sinensis) are also recognized to have anti-mutagenic and anti-cancer actions. The most abundant polyphenol in green tea is EGCG (epigallocatechin-3-gallate) which has also been the focus of pre-clinical and clinical research in a variety of health settings. EGCG have substantial free radical scavenging activity and protect cells from DNA damage caused by reactive oxygen species [68]. Tea polyphenols have also been shown to inhibit tumor cell proliferation and induce apoptosis in laboratory and animal studies [69] while in other studies, tea catechins have shown to inhibit angiogenesis and tumor cell invasiveness as well as modulate immune system function [70]. Some evidence from animal studies suggests that tea has a protective effect against stomach and colon cancers and the threat of cancer in number of organs is diminished by utilization of green and black tea or their primary catechins [71]. Furthermore studies have also found that green tea as well shields the body from harmful effects of radiation [25,32]. Although many of the potential beneficial effects of tea have been attributed to the strong antioxidant activity of tea polyphenols, the precise mechanism by which tea might help prevent cancer has not been established [69].
     
    3.10 Ginseng
     
    Panax ginseng is a perennial plant grown in China, Korea, Japan and Russia. The dried roots of the plants are used in traditional medicines to treat a variety of conditions, including cancer. Constituents of ginseng have been shown to inhibit the production of tumor necrosis factor in mouse skin, [72] inhibit the growth and proliferation of cancer cells in animal models, inhibit cell proliferation, induce differentiation, and stimulate interferon levels. Other tumor cell processes may also be interfered with by ginseng constituents [73].
     
    Research investigations conducted in Korea recommended that ginseng may decrease the threat of malignancies in humans [32]. Most effective form of ginseng is known to be its extract and powder compared to fresh sliced ginseng, ginseng juice, or ginseng tea, for diminishing the threat of cancer. In a large-scale, case-control study in Korea, researchers observed that the incidence of human cancer decreased steadily with duration of ginseng use and total lifetime use of ginseng [32,74]. Other studies report that ginseng hinders cancer development by disrupting with the DNA synthesis. Panax ginseng contains several active constituents which helps restart the natural killer cells that are injured during chemotherapy and radiotherapy, stimulate the macrophages and encourages formation of antibodies [25].
     
    3.11 Black cohosh
     
    Black cohosh is among the most frequently cited agent being used by breast cancer patients during their radiotherapy and chemotherapy. Black cohosh (Cimicifuga racemosa) is a shrub like plant commonly seen in the eastern forests of North America [11]. It has been used since centuries by Native American herbalist for health issues like menopausal symptoms, pre-menstrual discomfort and dysmenorrheas, as well as to induce abortion and numerous other problems. The herb was a chief component of the once famous patent medicine Lydia Pinkham’s Vegetable Compound and was also listed in the 19th century Pharmacopoeia. Drug stores offers a range of black cohosh preparations, supported by the recommendations of herbalists and traditional healers as being safe, effective and natural therapy for menopausal symptoms [11]. Black cohosh is being utilized by women who have been recommended to avoid HRT (Hormonal Replacement Therapy) by their doctors, who are at high risk for breast cancer or who have discontinued HRT after a diagnosis of breast cancer [11].

    A thorough and systematic scientific literature on black cohosh is amazingly sparse. Majority of studies have revolved around the herb’s effects on menopausal symptoms [75]. The active component(s) have not been definitively identified; triterpene glycosides (including 27 deoxyactein, acetein, and cimifugoside), have been assumed to be the vital constituent, but resins and caffeic, isoferulic and fukinolic acid also have been put forward as to having biological actions [11]. It is ambiguous whether the herb has estrogenic or anti-estrogenic activities with numerous studies in the literature posing considerable debate over the subject [11,76]. Research discloses only a small number of studies testing the effects of black cohosh on breast cancer cells with contradictory conclusions, few reporting increase and others no change or decrease in the development of breast cancer cells in culture [11].

    Sara et al. cautioned that black cohosh should not be considered to be a harmless herb that is insignificant to the health of cancer patients or to the outcome of conventional cancer therapy.

    Unless the outcome of black cohosh is vividly clear, the utilization of this and similar herbal product by breast cancer patients must be discouraged [11]. While another study by Einbond et al. indicated that relatively low concentrations of actein or the ethyl acetate, fraction of black cohosh, can cause synergistic inhibition of human breast cancer cell proliferation when combined with different classes of chemotherapy agents [77].
     
    4. Traditional Chinese medicine (TCM)
     
    Another form of treatment considered part of CAM is Traditional Chinese medicine (TCM) this originated during ancient China and has evolved over thousands of years. It is based on Chinese medical principles primarily the energetic qualities of the herbs rather than the chemical properties as understood by Western pharmacology [78]. TCM has been gaining immense attention as well as acceptance and has presented a central platform to health care in many countries. In Taiwan, Chinese herbal products (CHP) have been an imperative part of health care for past several decades [79] and are fully compensated under the current National Health Insurance (NHI) system. There are over 2,000 different kinds of herbs (of which about 400 are commonly used).

    Past clinical trials have established that Jia-wei-xiao-yao-san (Augmented Rambling Powder), which is the principle and most commonly approved method for managing breast cancer in Taiwan, may be an effective treatment for diminishing psychological (anxiety and depression) signs and symptoms in postmenopausal women [80,81]. Among the best, principally agreed method for managing breast malignancies, Gui-pi-tang (Ginseng and Longan Combination), Tian-wang-bu-xin-dan (Ginseng and Zizyphus Combination), and Suan-zao-ren-tang (Zizyphus Combination), all of which have an extensive record of utilization, are believed to nurture the blood and soothe the nerves and are quite commonly prescribed by TCM doctors to relieve or minimize sleep disorder [82]. Other frequently approved methods are often for alleviating gastrointestinal distress (Ban-xia-xie-xin-tang, or Pinellia Combination), reduced appetite (Xiang-sha-liu-jun-zi-tang, or Vladimiria and Amomum Combination), exhaustion, weakness (Bu-zhong-yi-qi-tang, or Ginseng and Astragalus Combination), palpitation (Ren-shen-yang-rong-tang, or Ginseng Nutritive Combination), or enlargement or inflammation of lymph nodes (San-zhong-kui-jian-tang, or Forsythia and Laminaria Combination) [80].

    However it is evident from Lai et al. study that TCM doctors in Taiwan recommend herbal remedies primarily for decreasing psychosocial sufferings and symptomatic distress [82]. Nonetheless, it is yet to be explained whether commonly prescribed CHPs comprising of ren shen (Panax ginseng-radix) and dang qui (Angelica sinensis-radix) for tumor management are anticipated by TCM doctors to reduce the treatment coupled toxicity or to improve the cancer resulting illness/symptoms. Further studies are necessary to evaluate such preparations and its efficacy as an add-on treatment for women undergoing conventional breast cancer management [82].
     
    4.1 Anti-breast cancer agents discovered from Chinese herbal medicine
     
    A number of anti-breast cancer agents have been discovered from Chinese herbal medicines (CHM), although some of the mechanisms of action have still not been clarified. The findings from some of the studies are summarized below;
     
    4.1.1 Alkaloids: Alkaloids exist widely in CHM and natural products. It has been used in the treatment for many diseases with a long history. The anti-breast cancer activity of more than 20 alkaloids isolated from CHM has been investigated in vitro by determining the inhibitory activity against growth of human mammary cancer cell line BCAP [83]. Yang et al. reported that berbamine and camptothecin demonstrated significant inhibition for the growth of human mammary cancer cell line BCAP cell while Rescinnamine and tomatidine were found to have weak inhibition [83,84]. The study supported the potential in these ingredients as leading compounds for anti-tumor drugs in the future [84].
     
    4.1.2 Coumarins: About forty coumarin compounds isolated from the traditional CHM have been screened for their antitumor activity, It was found that bergapten, cnidilin, dicoumarol and notoptol exhibited weak inhibition for the growth of BCAP cell line, The inhibitory effects of psoralen and quercetin on the proliferation of human breast cancer cell lines MCF-7 were found to be able to inhibit proliferation [84].
     
    4.1.3 Flavanoids, and Polyphenols: Franek and Zhou et al. reported baicalin (antipyretic) Flavins scutellarin (a circulatory stimulant) and two extracts from salvia miltiorrhiza (SM-470, circulatory stimulant) and camellia sinensis (Cam-300, antipyretic), inhibited the proliferation of the human breast cancer cell lines MCF-7 and T-47D, with baicalin being the most potent inhibitor [85]. Moreover, the combination of these compounds from different botanical classes offers enhanced therapeutic Benefits such as the combination of SM-470 (circulatory stimulant) with scutellarin, cam300 or baicalin, augmented the inhibition of cell proliferation [84].

    Eulalia et al. reported Resveratrol (RES), a chemo-preventive molecule, to be able to inhibit the proliferation of tumor cells of different etiologies [86]. The study showed that RES altered the cell cycle and induced apoptosis in MCF-7 breast tumor cells by interfering with the estrogen receptor (ER)-dependent phosphoinositide 3-kinase (PI3K) pathway. Curcumin was also found to inhibit the proliferation as well as induced apoptosis of MCF-7 cells [84,86].
     
    4.1.4 Terpenoids: The medicinal herb feverfew (Tanacetum parthenium), has been used as a folk remedy for the treatment of migraine and arthritis for long time [87]. Parthenolide, a sesquiterpene lactone, is considered as the primary bioactive compound in feverfew. Wu et al. measured the inhibitory activity of parthenolide against two human breast cancer cell lines (Hs605T and MCF-7) and one human cervical cancer cell line (SiHa) [84,87]. Among the tested constituents of feverfew, parthenolide demonstrated the highest inhibitory effect [87].

    Zhang et al. studied the inhibitory effects of Ursolic acid (UA), apentacyclic triterpene acid on MCF-7 cell apoptosis [88]. The results showed that twenty-four hours after UA treatment, apoptotic cells increased dose dependently and the morphology changes of MCF-7 cells displayed many hallmark features of apoptosis, including chromatin aggregation and fragmented nuclei [84,88].
     
    4.1.5 Quinone and other chemical classes: Plumbago zeylanica Linn. (Plumbaginaceae) has been used for treatment of some tumor diseases in Chinese herbal medicines with long history, of which plumbagin [89] is one of very important bioactive components. Liu et al also observed the anti-tumor activity of plumbagin in vitro. The results of which showed that plumbagin had significant cytotoxic effect however this promising result needs further exploration [84,89].

    Another research study documented the mechanism of action and the effects of Artemisinin and its analog artemisunate on the proliferation of human breast cancer MCF-7 cell line. However, artemisinin had weaker effect on the proliferation of MCF-7 cell, while artemisunate effectively inhibited the proliferation of MCF-7 with higher apoptosis in vitro [84].
     
    4.1.6 Dandelion: or Taraxacum officinale (TO), have a history of use in Chinese, Arabian and Native American traditional medicine, to treat a variety of diseases including cancer. To date, however, very few studies have been reported on the anti-carcinogenic activity of TO. Sophia Sigstedt et al. 2008 in her study investigated on three aqueous extracts prepared from the mature leaves, flowers and roots of Taraxacum officinale and its effect on tumor progression, proliferation and invasion [90]. It concluded that the crude extract of dandelion leaf decreased the growth of (Michigan cancer foundation) MCF-7/AZ breast cancer cells, whereas the aqueous extracts of dandelion flower and root had no effect on the growth [90].
     
    4.1.7 Vinca rosea: (Catharanthus roseus) comprises of vinca alkaloids, which were the first phyto-constituents ever used to treat cancer. Research has led to the discovery of more than 70 alkaloids, which include vinblastine, vincristine (leurocrystine), alstonine, ajmalicine and reserpine etc. Vincristine is frequently administered in combination with other anticancer medications to treat cancers of the breast, lung, bladder and the cervix [25,91].
     
    4.1.8 Ochrosia elliptica: Ellipticine is one of the simplest naturally occurring alkaloids from the leaves of the evergreen tree Ochrosia elliptica, which behaves as a powerful anticancer agent. Ellipticine and its offshoots are used to treat cancers of the breast and the kidney. Lipophilic derivatives of ellipticine operates by binding to the DNA [25,92].
     
    5. Herbal Remedies: Adverse Effect and Drug Interaction
     
    Unlike conventional drugs, herbal products are not tested with the scientific rigor required of conventional drugs, nor are they regulated for purity and potency [93]. Thus, some of the adverse effects and drug interactions reported for herbal products could be caused by impurities (e.g., allergens, pollen and spores) or variability in preparation. In addition, the potency of an herbal product may increase the possibility of adverse effects [93].

    Taking example of Echinacea, although it is relatively safe, researchers cautioned that it may cause liver damage or suppress the immune system if used for more than 8 weeks. According to their recommendation, people taking medications known to cause liver toxicity, such as anabolic steroids, amiodarone (a drug for heart rhythm problems), and the chemotherapy drugs methotrexate and ketoconazole, should avoid echinacea use [33].

    Similarly, cat’s claw lowers blood pressure, causes sleepiness, and diarrhea. People who are taking blood pressure medicines, blood-thinning medications, hormones, or insulin should be cautioned of possible drug-herb interaction (American cancer society) ginseng with increased heart rate, nausea, headaches. Since ginseng may have steroid/hormone like effects, some health professionals show concern against its use particularly in women who have had breast or endometrial cancer [25]. Flaxseed on the other hand is associated with bowel obstruction and bleeding disorder. Burdock interacts with anticoagulant/antiplatelet drugs, slowing blood clotting and increasing the chances of bruising and bleeding [25].
     
    6. Conclusion/Way Forward
     
    There has been a recovery of attention and interest, both scientifically and in terms of recognition, in the consumption of natural approaches in treatment of chronic diseases. Science has long accepted the importance of natural substances, such as digitalis, aspirin, penicillin, insulin, steroids, etc. Experimentations have shown that herbal drugs can play anticancer role by stimulating apoptosis and differentiation, augmenting the immune system, hindering angiogenesis and reversing multidrug resistance. Nevertheless, the mechanism of the anticancer function has not yet been completely illuminated. Given that, several herbal medicines have not been tested comprehensively or even undergone basic research, often there is limited, insufficient data concerning the possible hazards and benefits of their consumption. In spite of the accepted perception of herbs as being safe, improves survival and quality of life, yet, a range of unfavorable events related with their consumption alone or in combination with standard conventional cancer treatment has been documented including the incidence of severe bone marrow depression.

    Further research is needed to explore the molecular mechanism of herbal drugs including carefully controlled trials, establishing which constituents are effective, which will offer precious evidence for investigating and developing anticancer drugs in the future. A combined research and clinical program of integrative medicine with the medical and public health communities coming together to become more involved in this dialogue is needed.
     
    Table 1: The Anti-Breast Cancer Agents and Its Effects
    Categories Active Agents Effects
     

     

    Alkaloids
    Berbamine Anti-mammary cancer
    Camptothecin Anti-mammary cancer
    Rescinnamine Anti-mammary cancer
    Tomatidine Anti-mammary cancer
     

     

     

    Coumarins
    Bergapten Anti-breast cancer
    Cnidilin Anti-breast cancer
    Dicoumarol Anti-breast cancer
    Notoptol Anti-breast cancer
    Psoralen Estrogen-like activity
    Quercetin Estrogen-like activity
     

    Flavonoids and
    polyphenols
    Baicalin Anti-breast cancer
    Scutellarin Anti-breast cancer
    Resveratrol Interfering PI3K pathway
    Curcumin Inhibit transcript of VEGFR and b-FGF
     

    Terpenoids
    Parthenolide Anti-breast, anti-cervical cancer
    Ursolic cid Anti-breast cancer
     

    Quinone and other
    chemical classes
    Plumbagin Anti-breast cancer
    Artemisinin Anti-breast cancer
    Artemisunate Anti-breast cancer
     
    Table constructed using data from [42] Lisha Y, Rui A, Kun L, Xinhong W (2013) Anti-Breast Cancer Agents from Chinese Herbal Medicines. Mini-Reviews in Medicinal Chemistry 13: 101-105.
     
    References





























































































     
     
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