Natural Products in Cancer Chemoprevention and Chemotherapy

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K.G. Ramawat and Shaily Goyal

Abstract Medicinal plants are an important source of diverse chemical compounds that have been used for the past several centuries in the treatment of cancer. About 25% of drugs in the modern pharmacopoeia are derived from plants, including several anticancer drugs currently in clinical use such as vincristine, vinblastine, pacli-taxel, podophyllotoxin, camptothecin and combretastatin. These natural products, their derivatives and analogues based on these drugs constitute an arsenal against various types of neoplasms. The traditional use of plants provides a lead for cancer chemopreventive molecules. The development of new derivatives from bioactive compounds of food origin has been a viable way to reduce toxicity and increase their effectiveness against cancer. The combined efforts of botanists, pharmacologists, chemists and biologists are required to discover new effective drugs to fight cancer. An evaluation of the mode of action of these bioactive molecules will be helpful in designing novel drugs targeting mitosis. This article discusses natural products currently in clinical use, and under clinical trials, for cancer chemotherapy and chemoprevention.

Keywords Betulinic acid • Chemoprevention • Genistein • Podophyllotoxin • Resveratrol Taxol Vincristine

10.1 Introduction

About 12.5% of the 422,000 plant species of higher plants are known as medicinal plants and constitute a principal source of bioactive molecules. As compared to this, a very low proportion (0.1 to 5%) of microorganisms has been explored for the production of secondary metabolites. These figures may increase as many plants, and most microorganisms, have not yet been screened for their biological properties [1]. The proportion of medicinal plants to the total documented species

Laboratory of Biomolecular Technology, Department of Botany, M. L. Sukhadia University, Udaipur-313001, India e-mail: [email protected]

K.G. Ramawat (ed.), Herbal Drugs: Ethnomedicine to Modern Medicine, DOI 10.1007/978-3-540-79116-4_10, © Springer-Verlag Berlin Heidelberg 2009

in different countries varies from 4.4 to 20% [2]. About 25% of drugs in the modern pharmacopoeia are derived from plants, and many others are synthetic analogues built on prototype compounds isolated from plants. Up to 60% of prescribed drugs in the Western world contain plant products or their derivatives [3]. In India, 1100 species are recognised as a source of raw material for Ayurvedic and Unani formulations [4]. Medicinal plants and their extracts have significant export value in some developing countries like India and China. Commerce of medicinal plants involves trading herbs, their extracts, and value-added products [5-7]. The purified active principle of several medicinal plants provides some of the most potent medicines used against several types of neoplasms, e.g. vincristine, paclitaxel [8-10]. The majority of these are complex natural products, and the chemical synthesis of chiral molecules is not economically feasible [11].

Drug discovery from medicinal plants has evolved with our civilisation. Herbs have been used to treat various types of tumours and other disorders for thousands of years [7]. The scientific basis for such use is not known to herbalists, but scientific validation has been done for many such drugs in recent years [12]. In the past few decades, significant advances in experimental methodology and molecular biology have enabled researchers to investigate the potential use of natural secondary products to treat or manage a plethora of chronic diseases, including various types of cancers [13]. Cancer represents one of the most severe health problems worldwide, and the search for more effective anticancer agents continues. Cancer alone caused over six million deaths in 2000, affecting over ten million people worldwide [14]. Cancer is the second leading cause of death in the United States, after cardiovascular diseases [15]. Carcinogenesis involves a complex interplay between genes and the environment, and multiple cumulative genetic changes are required for the transformation of normal cells into fully malignant cells; changes in several fundamental cell physiological characteristics take place during malignancy [16]. Essentially, self-sufficiency in growth signals, insensitivity to growth inhibitory (antigrowth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis are the main characteristics of tumourigenesis [17]. Disturbances in complex molecular events within cells involves growth-factor-signalling pathways (e.g. platelet-derived growth factor, epidermal growth factor and SOS-Ras-Raf-MAPK-cascade), transcription factors (e.g. NF-kB and AP-1), apoptotic signalling proteins (e.g. caspases, polyadenosine-5'-diphosphate ribose polymerase, Bcl-2 and Bcl-X1), protein kinases (e.g. mitogen-activated protein kinases), cell cycle proteins (e.g. cyclins, cyclin-dependent kinases and retinoblastoma proteins) and cell adhesion molecules (e.g. integrins, selections, cadherins, intercellular adhesion molecule and vascular adhesion molecule). However, despite the large amount of information on signals involved in tumourigenesis, effective drugs to control or prevent it are not available [17].

Secondary anticancer metabolites and their derivatives finding their way to clinical trials are mostly natural products of plant origin [18-20]. Generally natural products are screened against cancer to find a new weapon to fight this scourge. During the first phase (1960-1982) of evaluation of plant extracts against cancer, mainly leukaemia, the anticancerous property of taxol was established by the Na tional Cancer Institute (NCI) in the USA. In the second phase, NCI began a new programme in 1985 to evaluate extracts prepared from microorganisms, plants and marine products against an array of 60 different types of cancer cell lines, including those from solid tumours and leukaemia [21].

10.2 Cancer Chemoprevention

Chemoprevention and functional foods are new emerging areas in the prevention of diseases. Chemoprevention is defined as the use of synthetic or natural agents, alone or in combination, to block the development of cancer in human beings. Plants, herbs, vegetables and spices, used in folk and traditional medicine, have been accepted as one of the main sources of cancer chemopreventive drug discovery and development (Fig. 10.1) [22]. Carcinogenesis is a multistage process by which a normal cell is transformed into a cancerous cell. The process of transformation involves initiation by DNA damaging agents, promotion of cell proliferation, and progression involving additional genetic alterations. Chemopreventive molecules target each of these steps including anti-initiation strategies (e.g. DNA repair, detoxification, free-radical scavenging and carcinogen metabolism) and an-tipromotional/antiprogression strategies (e.g. free-radical scavenging, proliferation suppression, differentiation induction, immunity enhancement, inflammation reduction, increase in apoptosis, altered gene expression and decrease in angiogene-sis) [20, 23]. No toxicity is expected from a chemopreventive agent because of its long history of human consumption as herbal medicines, botanical dietary supplements or edible plants [20, 24, 25]. Bioactive components of dietary phytochemi-cals with chemopreventive properties include curcumin, genistein, resveratrol, dial-lyl sulphide, S-allyl cysteine, allicin, lycopene, capsaicin, diosgenin, (6)-gingerol, ellagic acid, ursolic acid, silymarin, anethol, catechins, eugenol, isoeugenol, isoth-iocyanates, indol-3-carbinol, isoflavones, phytoestrols, folic acids, b-carotene and flavonoids [26].

Several plant-derived compounds are in clinical trials as potential chemopre-ventive agents for various types of cancers, including curcumin (phase I colon), genistein (phase I breast and endometrial), soy isoflavonoids (phase II prostrate), indole-3-carbinol (phase I breast recurrence), perillyl alcohol (phase I breast), various forms of retinoic acid, phenethyl isothiocyanate (phase I lung), green tea/epigallocatechin gallate (phase II bladder and breast), and resveratrol (phase I and II) [20, 27, 28]. Details about these bioactive molecules are given in this book and elsewhere [29].

Dietary bioactive food components that interact with the immune response have considerable potential to reduce the risk of cancer. The reduction of chronic inflammation or its downstream consequences may represent a key mechanism whose effects can be reduced by targeting signal transduction or through antioxidant effects. Some of the most important immunomodulators are phytochemicals such as the polyphenols, epigallocatechin gallate (EGCG) and curcumin [30, 31]. Oxidative

OH O isoliquiritigenin

OH O isoliquiritigenin ho.

oh o genistein ho oh oh o genistein oh ho

oh o flavopiridol

Fig. 10.1 Cancer chemopreventive compounds

och3 curcumin h CO

/•v o^Y^V oh epigallocatechingallate IL ^^h o^Y^V oh epigallocatechingallate IL ^^h

ho capsaicin

O OH

O OH

gingerol

gingerol oh o flavopiridol

Fig. 10.1 Cancer chemopreventive compounds

o ho stress and associated mechanisms involving inflammation, aberrant signalling pathways, and gap junction intercellular communications is increasingly associated with the pathogenesis of various chronic degenerative disorders such as atherosclerosis, neurodegeneration and cancer [32]. The consumption of fresh fruits, vegetables and teas has the capacity to reduce the risk of cancer.

Polyphenols are the most abundant antioxidants in the diet. Despite their wide distribution in plants, the beneficial health effects of dietary polyphenols have been recognised rather recently. Until the mid-1990s, the most widely recognised antiox-idants were vitamins, carotenoids and minerals. Research on flavonoids and other polyphenols for their biological activity, including antioxidant properties and their chemopreventive effects, appeared after 1995 [33, 34]. One of the major difficulties in establishing a correlation between polyphenols and their health benefits is the presence of large numbers of polyphenolics in food [35] having different bio-

logical activities [36]. Major differences in the bioavailability of phenolics have, by now been well established and the influence of structural factors is better understood [37].

Resveratrol (3,5,4-trihydroxy trans-stilbene), a polyphenol, is present in black grapes and its preparations like red wine [38, 39]. The ethyl-acetate-soluble extract was found to inhibit cyclooxygenase-1 (COX-1) enzyme (88% inhibition at 69 |g/ml). Resveratrol has been isolated from several species of the families Vi-taceae, Dipterocarpaceae, Gnetaceae and Leguminosae. Apart from its cardiopro-tective effects, resveratrol exhibits anticancer properties as demonstrated by its ability to suppress proliferation of a wide variety of neoplasms, including lym-phoid and myeloid cancers, multiple myeloma, and cancers of the breast, prostate, colon, stomach and pancreas [40]. The growth inhibiting effects of resveratrol are mediated through cell cycle arrest [41]. Resveratrol is in phase I clinical trials for colon cancer (www.clinicaltrials.gov/ct/show/nct00256334) and against AIDS (www.ihv.org/clinicaLtrials/thera_vacc2.html). Details about the chemistry and production of resveratrol in Vitis cell cultures [39], epidemiological studies correlating consumption of red wine containing polyphenols like resveratrol and cardiovascular diseases [42, 43], and biological activities including anticancer properties of resver-atrol are discussed elsewhere [44-46] and in this book.

Tea polyphenols are widely consumed as non-alcoholic beverages. Some of the nutrients identified as chemopreventive agents in prostate cancer are green tea polyphenols. EGCG, derived from Camellia sinensis, has been shown to inhibit a variety of processes involved in cancer cell growth, survival and metastasis [47]. Of the tea polyphenols, EGCG has been most extensively investigated because of its relative abundance and strong cancer-preventive properties, particularly in the chemoprevention of breast cancer [48]. Details about tea polyphenols are given elsewhere [49] and in this volume.

Genistein, an isoflavonoid found with a large number of other isoflavonoids in several members of the family Fabaceae, particularly in Glycine max, has been established as a prostate cancer chemopreventive agent [50]. Genistein in the diet results in increased apoptosis in the prostate [51, 52]. Genistein-induced apoptosis involves activation of calpain, caspase 7, and poly (ADP ribose) polymerase [52].

Curcumin (diferuloylmethane) is a polyphenolic compound present in rhizomes of Curcuma longa, commonly used in Indian cooking. Although the broad curative properties of curcumin have been known for centuries, its potential anticancer and chemopreventive properties have been established only recently [53, 54]. Details are given elsewhere in this book.

Gingerol or (6)-gingerol, the phenolic substance responsible for the spicy taste of fresh ginger (Zingiber officinale), has diverse pharmacological effects, such as being antioxidant, anti-apoptotic and anti-inflammatory. Though its use dates back 2500 years, its anticancer and chemopreventive properties came to light only recently [55]. Inhibition of COX2 expression has been co-related as a molecular basis for its antitumour effects [56].

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is responsible for the piquancy of chilli pepper (Capsicum annuum). In experimental animals, it is suspected to act as a carcinogen due to its irritant properties. However, other studies indicated chemo-preventive and chemoprotective effects as capsaicin inhibits transcription factors (NF-kB, STAT3) [57] and angiogenesis [58].

Flavopiridol is a semisynthetic flavonoid and has been shown to be a potent inhibitor of cyclin-dependent kinases [59]. Flavopiridol also induces apoptosis, suppresses inflammation and modulates the immune response [17]. Thus, it may be concluded that the daily diet has an important role in cancer chemoprevention, and the cancer death rate could be reduced to approx. 35% by proper diet alone [60]. Bioactive molecules present in the diet influence all levels of metabolism, including epigenetic and genetic (transcription and translation levels). However, this requires scientific validation by modern tools and has become evident in plants such as ginger [61] and saffron [22].

10.3 Anticancer Drugs from Microorganisms

The search for effective compounds from microorganisms is more recent and not based on ethnobotanical records. Following the discovery of Penicillin from Penicillium flavum, microorganisms were explored for therapeutically significant molecules. A number of small-molecule drugs have been approved by the FDA, including 17% of microorganism origin out of 126 approved since World War II; the first of them was actinomycin D [62].

Mostly products from Actinomycetales were isolated, including daunorubicin and its derivative doxorubicin, which are still used against breast cancer. New derivatives produced were epirubicin, pirirubicin, idarubicin and lastly valrubicin. Cancer cell growth is affected by the inhibition of topoisomerase II. Bristol-Myers developed another important anticancer agent of Actinomycetales origin -bleomycins. Mitomycin C, mithramycin, streptozotocin, pentostatin and calicheam-icin are the other potent compounds in use, except the last one (Fig. 10.2).

Antibiotics are defined as low-molecular-weight organic natural products (secondary metabolites or idiolites) made by microorganisms which are active at low concentrations against other microorganisms. In 1995, about 12,000 antibiotics were known; 55% were produced by Streptromyces (Actinomycetes), 11% from other Actinomycetes, 12% from non-filamentous bacteria, and 22% from filamentous fungi. Many more new products are still being discovered from microorganisms. About 350 antimicrobials are available on the market for various human diseases. The antibiotic category includes cephalosporin (45%), penicillins (15%), tetracyclines (6%), macrolides (5%), aminoglycosides, ansamycins, glycopeptides and polyenes [63]. Of the 25 top-selling drugs in 1997, 42% were natural products or derived from natural products [64], of which antibiotics contributed 67% of sales (US$55 billion world market). Besides antimicrobial activity, other properties of antibiotics have been explored. An extremely important concept for the further drug development of natural products is that a compound possesses more than one biological activity [65].

10.4 Anticancer Drugs from Plants

More than 90 drugs are commercially available for cancer therapy, of which 62% are derived from natural products, excluding compounds like interferon [19]. Cancer or neoplastic conditions are poorly defined in ancient traditional or folklore medicine. Hence, leads are not available from such literature. Anticancer agents from plants which are currently in clinical use are Catharanthus roseus alkaloids (vinblastine and vincristine), epipodophyllotoxins from Podophyllum species, taxanes from Taxus spp., camptothecins from Camptotheca, and others (Fig. 10.3) [9, 21, 62, 66].

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