Herbal Drugs: A Twenty First Century Perspective Rakesh K Sharma, Rajesh Arora
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SECTION 1
Medicinal Plant Biodiversity, Standardization of Herbal Bioresources and Phytochemistry

Herbals for Human Health and Disease: Prospects and Challenges in 21st Century1

P Chirangini,
Amit Kumar,
BN Pandey,
GJ Sharma,
KP Mishra

ABSTRACT

It was well known to ancient world that plants are a rich source of a variety of chemicals with nutritive and therapeutic properties. In modern era, herbals are seen as potential medicine for a variety of diseases often viewed to supercede the pharmacological efficacy of allopathic drugs. There has been a striking increase in use of herbals in both developing and the developed countries due to their natural origin and minimal or no side effects. World-over, the pharmaceutical companies and research organizations are focussing on the vast untapped potential of herbals as potent drugs. Over the decades, several drugs have been sourced and isolated from herbal medicine, e.g. reserpine, vincristine and vinblastine. Neem and turmeric have attracted much attention and have been patented recently. This article presents an overview of growing interest in herbals in the area of radioprotection, cancer prevention and therapy. Research from our laboratory has shown that triphala, a combination herbal formulation, has the ability to kill breast cancer (MCF 7) cells, but it spares normal cells such as spleen cells, lymphocytes, liver cells and normal breast cells (MC H10). Results have shown that toxic effects of triphala are mediated through reactive oxygen species and executed through apoptotic pathways. These results have generated new excitements for prospects of cancer treatment. Today, the emphasis has tilted from cancer treatment to cancer prevention, mainly because of our realization that many phases of cancer induction process are influenced by nutrition. Therefore, demand is increasing for proper dietary recommendations. Control of expression of genes by phytochemicals and, consequent, protection against cancer is under active debate. In addition, our research has shown that eugenol effectively protects against radiation oxidative damage of liposomal and microsomal membrane. Recent findings from our laboratory, along with a highlight of the emerging scenario in herbal research relevant to nuclear research program have been dealt with in this article.
Since we have entered the 21st century with the need of enforcement of GATT, and escalated competition, to adapt to soon-to-change-scenario, the pharma industry is undergoing a sea change. The Indian pharmaceutical industry is definitely looking forward to aggressive herbal marketing. But, challenges are many before realizing the dream of safe and potent drug for effective treatment of patients and improvement of the quality of life. There remains a challenge of developing a scientific basis of herbal medicine and, therefore, clinical research is highly warranted. Moreover, translating therapeutic dietary recommendations into effective interventions is a real challenge. However, the advent of biotechnology, human genome knowledge and bioinformatics technology will certainly open new frontiers for treatment of diseases and provide enormous new opportunities for the growth of herbal industry.
KEYWORDS: Antioxidants, Cancer, Herbal Drugs, Radioprotection  
INTRODUCTION
Ancient people were fully aware of the rich potential of herbs for curing different types of ailments. Herbs belong to general botanicals of various types which are also often the aromatic plants, used especially in medicine or as seasoning. Herbs may be used directly as teas or extracts (herbals) and they may be used in 2the production of drugs. The study or use of such medicinal herbs to prevent and treat diseases and ailments or to promote health and healing is commonly known as herbal medicine. A drug or preparation made from a plant or plants and used for any of such purposes is better known as a herbal drug.
The practice of herbal medicine has existed since prehistoric times as the primary form of medicine. In this space age where technology has very much advanced, herbal medicine still flourishes and is finding exceptional acceptance in both the developing and the developed countries due to its natural origin and lesser side effects (Chopra et al., 1956). Over 80,000 species of plants are in use in herbal medicine throughout the world. Presently, approximately 25 percent of the prescription drugs sold in the United States are plant-based. Many more herbal ingredients are present in drugs, such as laxatives. Among the more popular remedies are: ginseng for increasing the stamina and as a mild sedative; St. John's-wort for mild depression; Echinacea to aid the immune system and alleviate colds; kava to calm anxiety and treat insomnia; saw palmetto for enlarged prostate; and Ginkgo biloba to improve short-term memory. Some people have used botanicals in an attempt to stave off serious illnesses such as AIDS and cancer.
 
Biological Background of Herbal Drugs
All plants produce chemical compounds as a part of their normal metabolic activities. These can be split into two broad categories—primary metabolites, which include sugars, fats, and amino acids, and secondary metabolites, which are much more specialized substances with a wide variety of functions in the organisms that make them. Primary metabolites are found in all plants, but secondary ones in a much narrower range—some only in a particular genus or species. The functions of secondary metabolites are extremely varied, with some functioning as toxins, some to attract insects, and some with more esoteric functions. It is these secondary metabolites which can have therapeutic actions in humans, and which can be refined to produce drugs—inulin from the roots of dahlias, quinine from the cinchona, morphine and codeine from the poppy, and digoxin from the foxglove are all such examples.
 
RESOURCES
Besides wide-spread use of botanicals as medicinal products in developing countries, such products are fast becoming a part of the integrative healthcare systems of the industrialized nations, known as “complementary and alternative system of medicines” (CAM). A number of herbal traditions have come to dominate the practice of alternative medicine. For example, the western herbal tradition based on Greek, Roman and medieval sources, the essentially ayurvedic tradition of India and the Chinese herbal medicine.
 
Indian Scenario
Botanicals or phytomedicines have always been a major component of traditional systems of healing in developing countries, which have also been an integral part of their history and culture. The ancient Indian system of medicine, Ayurveda and Siddha are such examples.
 
World Scenario
Traditional Chinese medicine continues as a distinct branch of modern medical practice, and within China, along with acupuncture, it is an important part of the public health care system where it has been in documented use for over 2,500 years. The use of traditional herbal remedies as alternative medicine plays a significant role in South Africa also, where it forms a part of the culture and beliefs of the indigenous population and also features significantly in primary health care (Hutchings et al., 1996).
 
MAJOR HERBALS IN DISEASES
Many of the pharmaceuticals currently available have a long history of use as herbal remedies, including (among many others) opium, aspirin, digitalis, and quinine. While purification and quantification of these plant extracts makes them more predictable, and 3chemical processing can sometimes modify their effects in desirable ways, herbal remedies tend to have a more complex and subtle mix of chemicals, and can sometimes offer access to drugs, or combinations of drugs, that the pharmaceutical industry has not yet exploited. Some medicines that come from plants sources are given below:
Aspirin (acetylsalicylic acid), a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body is extracted from the bark of white willow tree, Salix alba. It is also used as an analgesic, antipyretic, and anti-coagulant.
Digitalis (composed of steroid glycoside and lactone, a cyclic ester) is one of several chemically similar drugs (digitoxin, digoxin, all from foxglove Digitalis purpurea and ouabain from Strophanthus gratus) used in the treatment of congestive heart failure, cardiac arrhythmias and also in the treatment of dropsy (edema).
Opium, a strongly addictive narcotic and analgesic drug, is prepared from the dried juice of unripe pods of the opium poppy, Papaver somniferum. It contains alkaloids, such as, morphine, codeine (phenan-threnes), and papaverine (benzylisoquinolines).
Quinine, a crystalline alkaloid, C20H24N2O2·3H2O, derived from certain Cinchona barks, is used in medicine to treat malaria.
 
HERBS AND CANCER
A substance with pronounced antioxidant and anti-inflammatory effects is anticipated to act as an anti-tumor promoter. A wide variety of phenolic substances derived from edible plants have been reported to retain such activities, which exert chemopreventive effect on carcinogenesis (Surh, 1999). A few examples of representative chemopreventive herbal ingredients with substantial antioxidative and anti-inflammatory properties are curcumin from turmeric (Curcuma longa Linn.), and gingerol from ginger (Zingiber officinale Roscoe).
 
Betulinic acid
Betulinic acid, a pentacyclic triterpene, isolated from various plant sources has therapeutic property. It has manifested anti-inflammatory and anti-HIV activities. Gopal et al., (2005) showed the cytotoxicity of betulinic acid on human chronic myelogenous leukemia (CML) cell line K-562, which is positive for Bcr-Abl. The rapid loss of mitochondrial membrane potential of K-562 cells upon treatment with this acid shows the direct activation of apoptosis at the level of mitochondria, overcoming the resistance of the high levels of expression of Bcr-Abl.
 
Curcumin
A yellow pigment present in the rhizome of turmeric and related species has a wide array of pharma-cological and biological activities (Ammon and Wahl, 1991). Anti-oxidant and anti-inflammatory effects of this compound have been assessed in various in vitro and in experimental animal systems. One of the most plausible mechanisms underlying the chemopre-ventive effects of curcumin involves suppression of tumor promotion. Thus, topical application of curcumin strongly inhibited 12-O tetradecanoyl-phorbol-13-acetate (TPA)-induced inflammation, hyperplasia, proliferation, generation of reactive oxygen intermediates (ROIs), oxidized DNA base modification and papilloma formation in mouse skin (Lu et al., 1993). Curcumin inhibited Cyclo-oxygenase-2 (COX-2) and lipooxygenase activities in TPA-treated mouse epidermis (Huang et al., 1991). Treatment of several human gastrointestinal cell lines with curcumin suppressed expression of COX-2 protein and mRNA, prostaglandin E2 production, and AP-1 (eukaryotic transcription factor) DNA binding induced by TPA or chenodeoxycholate (Zhang et al., 1999).
 
Diospyrin
Several quinonoids have been isolated from plants which are generally used in oriental herbal preparations. Diospyrin, isolated from many traditional medicinal plants, is a bisnaphthoquinonoid compound. It is known to possess antitumor activity in murine systems as well as in a variety of human tumor cell lines. Diospyrin derivatives selectively inhibit topoisomerase I enzyme and also inhibit 4spliceosome assembly. It has emerged as a potential ‘lead molecule’ for the development of new drugs against cancer as well as several other diseases like leishmaniasis, trypanosomiasis, malaria and tuberculosis. This compound has been reported to show inhibitory activity against murine tumor in vivo through liposomal encapsulation (Hazra et al., 2005).
 
Gingerol
The oleoresin from rhizomes of ginger contains [6]-gingerol (1-[40-hydroxy-30-methoxyphenyl]-5-hydroxy-3-decanone) and its homologues as pungent ingredients, that have a wide array of pharma-cological and physiological activities (Surh et al., 1998). Gingerol was reported to possess substantial antioxidant properties as determined by inhibition of phospholipid peroxidation induced by the FeCl3-ascorbate system and also of the xanthine oxidase activity (Aeschbach et al., 1994). When topically applied prior to each TPA treatment during the entire period of tumor promotion after the initiation with 7,12-dimethylbenz[a]anthracene, gingerol strongly inhibited mouse skin tumor formation (Park et al., 1998). Azoxymethane-induced intestinal tumo-rigenesis was ameliorated by dietary administration of gingerol (Yoshimi et al., 1992). A recent study by Bode et al., (2001) has demonstrated that [6]-gingerol inhibits neoplastic transformation and activation of AP-1 in mouse epidermal JB6 cells treated with epidermal growth factor.
 
Triphala
Triphala, a herbal drug consisting of the dried and powdered fruits of three plants, Terminalia chebula, Emblica officinalis and Terminalia bellerica in equal proportions, is an important medicine of the ‘rasayana’ group and is believed to promote health, immunity and longevity. This formulation, rich in antioxidants, is used to treat many diseases such as anemia, jaundice, constipation, asthma, fever and chronic ulcers. Recent studies from our laboratory have shown that Triphala possessed cytotoxic effects on human breast cancer cell lines (MCF 7 and T 47 D) differing in their p53 status and also on a transplantable mouse thymic lymphoma, barcl-95 (Sandhya and Mishra, 2005; Sandhya et al., 2005).
 
HERBS AND RADIOPROTECTION
Several plants have been used to treat free radical-mediated ailments and, therefore, it is anticipated that such plants may render some protection against radiation damage (Arora et al., 2005). So these radioprotective agents or radioprotectors have their potential for use within a radiation environment (during planned or unplanned radiation exposure), such as space exploration, radiotherapy and nuclear emergencies. Plants and their constituents with pharmacological activities like anti-emetic, anti-inflammatory, antioxidant, cell proliferative, wound healing and hemopoietic stimulatories have relevance to amelioration of radiation-mediated damages.
Listed below are some important herbs which have radioprotective efficacy:
 
Abana: A Herbal Preparation
Abana is a traditional herbal preparation, widely used in India for the treatment of heart ailments. Jagetia et al., (2003) studied the effect of 50 percent ethanolic extract on radiation-induced mortality in mice exposed to 10 Gy of γ-radiation. The highest protection against GI death was observed for 20 mg/kg abana. Acute toxic studies revealed that abana was non-toxic upto a dose of 1.6 g/kg, where no drug-induced mortality was observed. The LD50 dose of abana was found to be 1.8 g/kg body weight. This demonstrates the ability of abana as a good radioprotective agent and the optimum protective dose of abana was 1/90 of its LD50 dose.
 
Centella asiatica Linn.
An aqueous extract of Centella asiatica when used to protect Sprague Dawley rats against the adverse effects of low-dose ionizing radiation (2 Gy) rendered significant protection against radiation-induced body weight loss and conditioned taste, suggesting that this plant could be useful in preventing radiation-induced behavioral changes during clinical radiotherapy (Shobi 5and Goel, 2001). Centella asiatica extract (100 mg/kg body weight) administered orally has recently been shown to provide total body protection in mice against sub-lethal (8 Gy) 60Co gamma radiation (Sharma and Sharma, 2002).
 
Ginkgo biloba Linn.
An ethanol (30%) extract of the dried leaf of this plant, at a concentration of 100 μg/mL, was effective when tested on a culture exposed to clastogenic factors from plasma of human subjects exposed to irradiation (Emerit et al., 1995a). Treatment of recovery workers from the Chernobyl accident site was found to be effective when an oral dose of 40 mg/day was given 3 times daily for 2 months (Emerit et al., 1995b). An intravenous infusion of an ethanol extract of G. biloba leaves, at a dose of 100 mg/person was found to be effective on patients with vasogenic edema observed after irradiation of the brain (Hannequin et al., 1986).
 
Mentha piperita Linn.
Pre-treatment with Mentha piperita extract protected haematological constituents and serum phosphatases activity in Swiss albino mice against γ-radiation (Samarth et al., 2002a). The leaf extract of M. piperita was shown to provide protection against radiation-induced alterations in the intestinal mucosa of mice (Samarth et al., 2002b). M. piperita pre-treatment also protected against the radiation-induced increase in goblet cells/villus section and dead cells/crypt section in the jejunum of mice. Oral administration of M. piperita (1 g/kg body weight/day) prior to sub-lethal radiation exposure (8 Gy) was found to be effective against the chromosomal damage in bone marrow of Swiss albino mice (Samarth and Kumar, 2003). Irradiated animals exhibited chromosomal aberrations in the form of chromatid and chromosome breaks, centric rings, dicentric exchanges and acentric fragments, while animals pre-treated with M. piperita extract showed a significantly lesser number of aberrant cells. It also significantly increased GSH levels and decreased the lipid per-oxidation level in irradiated mice.
 
Ocimum sanctum Linn.
The radioprotective property of O. sanctum was reported for the first time by Uma Devi and Ganasoundari (1995). The optimal dose for protection was reported to be 50 mg/kg body weight (i.p. administration), while the acute LD50 was 6 g/kg body weight. Ganasoundari et al., (1997) studied the effect of O. sanctum on the survival of mice after whole-body lethal irradiation and compared it with WR-2721 (amifostine), a standard synthetic radioprotector. Their results indicated that O. sanctum promotes recovery and regeneration of hemopoietic progenitor cells in mice bone marrow suggesting that the herbal extract is a better radioprotector than the synthetic drug in terms of the protective dose and toxicity. The flavonoids, orientin and vicenin, were found to be equally effective in rendering protection against γ-radiation-induced lipid peroxidation in mouse liver. These compounds also significantly inhibited the Fenton reaction-induced OH radical activity under in vitro conditions (Uma Devi et al., 2000) and protected human lymphocyte chromosomes (Vrinda and Uma Devi, 2001).
 
Nigella sativa Linn.
It is commonly known as black cumin and is the main constituent of most of unani and ayurvedic drugs. It is known for antileshmanial, antimalarial, antiparasitic and have protective effect against nephrotoxicity. The ethanolic extract of this plant has been tested for antioxidant/radioprotective effects in vitro as well as in vivo. The extract has been found to inhibit radiation-induced reactive oxygen species (ROS), reactive nitrogen species (RNS), malondialdehyde (MDA) level in concentration dependent manner in splenic lymphocytes in vitro. The ethanolic extract of Nigella sativa showed protection against radiation-induced depletion in antioxidant enzymes [(superoxide dismutase (SOD) catalase, and glutathione peroxidase (GPx)] in liver and spleen homogenates of Swiss mice when fed orally (Rastogi and Mishra, 2005, unpublished data).
6
 
Ellagic Acid
Ellagic acid is a naturally occurring polyphenolic compound found in strawberries and raspberries. The role of ellagic acid (EA) and γ-radiation on the oxidative stress and subsequent cytotoxicity of tumor cells in vitro as well as in vivo and their sparing effects on normal cells was studied. Results suggest that combined treatment of tumor with EA and radiation enhances oxidative stress and cytotoxicity in tumor cells. EA protects normal cells against radiation damage. This may offer potential therapeutic benefit, which warrants clinical study for application in cancer radiotherapy (Bhosle et al., 2005a).
 
Prognostication of Radiotherapy in Cervix Cancer
The study was aimed to develop possible predictive response of cervical carcinoma in stage IIIA and B patients by evaluating the changes in physical parameter such as, membrane fluidity, biochemical parameters such as, intracellular calcium, antioxidant enzymes (SOD, Catalase, GPx) and apoptotic cell death in cervical cancer cells from patients after treating with the first fractionated dose of 2 Gy in radiation therapy protocol. Results suggest the usefulness of apoptotic index as a predictor of radiotherapy outcome in cervical tumor, and also point to a correlation between apoptosis and its associated biomarkers, membrane fluidity, intra-cellular calcium and SOD (Bhosle et al., 2005b).
 
FUTURE DIRECTION AND SCOPE
The herbal scenario in the 21st century is marked by stiff competition amongst the pharmaceutical industries. Such competition is prompted by the fact that herbal drugs are user-friendly due to their natural origin and lesser side effects.
The widespread use of herbs in traditional medicine has also prompted demands that herbal remedies be regulated as drugs to ensure quality standards and to prove its scientific basis. Clinical trials on any herb that has a health claim on its label should be conducted but medical testing, which is geared toward observing a particular active component, is difficult to apply to herbs, which may have many interacting ingredients. Debate over botanicals’ validity and safety as medicines and over the appropriate degree of government regulation continues. However, the real challenge lies in translating the therapeutic recommendations into effective interventions of these medicinal plants.
In spite of several biological activities being shown by the different herbal extracts, only a small percentage of the diverse plant resources have been investigated so far. If large-scale screening of these herbal extracts is done by developing efficient and reliable assay systems, then many of them may prove to be very efficient radioprotectors. Needless to say, development of a suitable radioprotector for nuclear emergencies, radiotherapy and occupational exposures would go a long way in the progress of nuclear technology.
Herbs hold promise not only for prevention but also for the treatment of various kinds of cancers. Although extensive data on chemopreventive potential of plants in both cell culture and animal models are available, clinical or epidemiological data in human population are limited.
With the advent of biotechnology, the unfolding of the human genome and the various tools of bioinformatics, new frontiers in the treatment of diseases like personalized medicine will open up and this will provide new scope and opportunities for the growth of herbal industry.
 
ACKNOWLEDGEMENT
The authors are grateful to the Board of Research in Nuclear Science, Department of Atomic Energy, Government of India for financial assistance.
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