1 INTRODUCTION India is a land of immense biodiversity in which two (Eastern Himalayas and The Western Ghats of India) out of twenty five hot spots of the world are located. This country is perhaps the largest producer of medicinal herbs and is rightly called the botanical garden of the world. It is generally estimated that in India over 6000 plants are used in traditional, folk and herbal medicine, representing about 75% of the medicinal needs of the Third World countries. Medicinal herbs as potential source of therapeutic aids has attained a significant role in health system all over the world for both humans and animals not only in the diseased condition but also as potential material for maintaining proper health. The market share of herbal products made in developing countries remains comparatively low due to lack of research and development and the huge investments in making standardized products. Though India has a rich biodiversity, the growing demand is putting a heavy strain on the existing resources. While the demand for medicinal plants is growing, some of them are increasingly being threatened in their natural habitat. For meeting the future needs cultivation of medicinal plant has to be encouraged. Today there are at least 120 distinct chemical substances derived from plants that are considered as important drugs currently in use in one or more countries in the world. Indeed, molecules derived from natural sources (so-called natural products), including plants, marine organisms and microrganisms, have played, and continue to play, a dominant role in the discovery of leads for the development of conventional drugs for various diseases. In terms of a modern research endeavor, drug development from plants must necessarily imply a multi- displinary approach. Plants are used medicinally worldwide as sources of many potent drugs. Traditional medical practitioners use a variety of herbal preparations to treat different kinds of diseases including microbial infections. (Gunther, 1952; Chopra, 1956; Gopalan, 1984; Bauddhaloka, 2005). The World Health Organisation (WHO) estimated that 80% of the population of developing countries relies on traditional medicines, mostly plant drugs, for their primary
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1
INTRODUCTION
India is a land of immense biodiversity in which two (Eastern Himalayas and The
Western Ghats of India) out of twenty five hot spots of the world are located. This country
is perhaps the largest producer of medicinal herbs and is rightly called the botanical
garden of the world. It is generally estimated that in India over 6000 plants are used in
traditional, folk and herbal medicine, representing about 75% of the medicinal needs of
the Third World countries. Medicinal herbs as potential source of therapeutic aids has
attained a significant role in health system all over the world for both humans and animals
not only in the diseased condition but also as potential material for maintaining proper
health. The market share of herbal products made in developing countries remains
comparatively low due to lack of research and development and the huge investments in
making standardized products.
Though India has a rich biodiversity, the growing demand is putting a heavy strain
on the existing resources. While the demand for medicinal plants is growing, some of
them are increasingly being threatened in their natural habitat. For meeting the future
needs cultivation of medicinal plant has to be encouraged. Today there are at least 120
distinct chemical substances derived from plants that are considered as important drugs
currently in use in one or more countries in the world. Indeed, molecules derived from
natural sources (so-called natural products), including plants, marine organisms and
microrganisms, have played, and continue to play, a dominant role in the discovery of
leads for the development of conventional drugs for various diseases. In terms of a modern
research endeavor, drug development from plants must necessarily imply a multi-
displinary approach. Plants are used medicinally worldwide as sources of many potent
drugs. Traditional medical practitioners use a variety of herbal preparations to treat
different kinds of diseases including microbial infections. (Gunther, 1952; Chopra, 1956;
Gopalan, 1984; Bauddhaloka, 2005).
The World Health Organisation (WHO) estimated that 80% of the population of
developing countries relies on traditional medicines, mostly plant drugs, for their primary
2
health care needs. Also, modern pharmacopoeia still contains at least 25% drugs derived
from plants and many others which are synthetic analogues built on prototype compounds
isolated from plants. Demand for medicinal plant is increasing in both developing and
developed countries due to growing recognition of natural products, being non-narcotic,
having no side-effects, easily available at affordable prices and sometimes the only source
of health care available to the poor. Medicinal plant sector has traditionally occupied an
important position in the socio cultural, spiritual and medicinal arena of rural and tribal
lives of India. Medicinal plants as a group comprise approximately 8000 species and
account for around 50% of all the higher flowering plant species of India. Millions of rural
households use medicinal plants in a self-help mode. Over one and a half million
practitioners of the Indian System of Medicine in the oral and codified streams use
medicinal plants in preventive, promotive and curative applications. There are estimated to
be over 7800 manufacturing units in India. In recent years, the growing demand for herbal
product has led to a quantum jump in volume of plant materials traded within and across
the countries. An estimate of the EXIM Bank puts the international market of medicinal
plants related trade at US $ 60 billion per year growing at the rate of 7% only (WHO,
2000).
Medicinal plants are important for pharmacological research and drug
development, not only when plant constituents are used directly as therapeutic agents, but
also as starting materials for the synthesis of drugs or as models for pharmacologically
active compounds. A significant number of modern pharmaceutical drugs are thus based
on or derived from medicinal plants. The need to document plant uses and attempt to
confirm their efficacy remains urgent. The term ethnopharmacology loosely describes the
field covering observation, identification, description and experimental investigation of
the effect of indigenous drugs and its ingredients is truly an interdisciplinary field of
research. Traditional medicine is a powerful source of biologically active compounds.
Ethnopharmacology has become a scientific backbone in the development of active
therapeutics based upon traditional medicine of various ethnic groups.
Ethnopharmacology is the survey of plants of a particular region or cultural tribe
depending on their use in traditional system by choosing a specific therapeutic target.
3
Screening program based on ethnopharmacological information has more success rate
than random screening (Papiya Bigoniya and Rana, 2008). Pharmacognosy is closely
related to botany and chemistry, both originated from the earlier scientific studies on
medicinal plants. A field concerned with the description and identification of drugs both in
whole state and powder along with their history, commerce, collection, preparation and
storage (Trease and Evans, 2008).
Medicinal herbs are moving from fringe to mainstream use with a greater number
of people seeking remedies and health approaches free from side effects caused by
synthetic chemicals. Recently, considerable attention has been paid to utilize eco-friendly
and bio-friendly plant-based products for the prevention and cure of different human
diseases. Considering the adverse effects of synthetic drugs, the western population is
looking for natural remedies which are safe and effective (Dubey et al., 2004). It is
documented that 80% of the world’s population has faith in traditional medicine,
particularly plant drugs for their primary healthcare. India is sitting on a gold mine of
well-recorded and traditionally well-practiced knowledge of herbal medicine. This country
is perhaps the largest producer of medicinal herbs and is rightly called the botanical
garden of the world. There are very few medicinal herbs of commercial importance which
are not found in this country. India officially recognizes over 3000 plants for their
medicinal value. It is generally estimated that over 6000 plants in India are in use in
traditional, folk and herbal medicine, representing about 75% of the medicinal needs of
the Third World countries (Rajshekharan, 2002).
Undoubtedly, the plant kingdom still holds many species of plants containing
substances of medicinal value which have yet to be discovered. India is a land of immense
biodiversity in which two out of eighteen hot spots of the world are located. India is also
one of the twelve mega biodiversity countries in the world. The total number of plant
species of all groups recorded from India is 45,000 (the total number may be even close to
60,000, as several parts of India are yet to be botanically explored). Of these, seed-bearing
plants account for nearly 15,000–18,000. India enjoys the benefits of varied climate, from
alpine in the Himalaya to tropical wet in the south and arid in Rajasthan. Such climatic
4
conditions have given rise to rich and varied flora in the Indian subcontinent. In order to
promote Indian herbal drugs, there is an urgent need to evaluate the therapeutic potentials
of the drugs as per WHO guidelines. Ironically, not many Indian products are available in
standardized form, which is the minimum requirement for introducing a product in the
western market (WHO, 2000).
The primary benefits of using plant derived medicines are that they are relatively
safer than synthetic alternatives, offering profound therapeutic benefits and more
affordable treatment. The use of medicinal plants in developing countries as a normative
basis for the maintenance of good health has been widely observed. Furthermore, the
increasing reliance on the use of medicinal plants in the industrialized societies has been
traced to the extraction and development of several drugs and chemotherapeutics from
these plants as well as from traditionally used rural remedies. Moreover, in these societies,
herbal remedies have become more popular in the treatment of minor ailments and also on
account of the increasing costs of personal health maintenance (Okigbo et al., 2009).
Some of the useful plant drugs include vinblastine, vincristine, taxol,
Turmeric Curcuma longa Curcumin Terpenoids Bacteria, protozoa
Plants have limitless ability to synthesize aromatic secondary metabolites, most of
which are phenols or their oxygen-substituted derivatives. Important subclasses in this
group of compounds include phenols, phenolic acids, quinones, flavones, flavonoids,
flavonols, tannins and coumarins. These groups of compounds show antimicrobial effect
16
and serves as plant defense mechanisms against pathogenic microorganisms (Das et al.,
2010). Antimicrobial activity of Cassia alata was noticed against E. coli and fungi
(Ikenebomeh et al., 1988). Water extract of Senna alata showed antimicrobial activity
against B. subtilis only but other reports of antimicrobial activity exists (Adebayo et al.,
1991, Ibrahim and Osman 1995).
Standard criteria for in vitro evaluation of antimicrobial activity of plants differ
among authors. Results obtained from antimicrobial efficacy of plant extract is often
difficult to compare with published results due to the influence of several factors, that is,
environment and climatic conditions during plant growth, choice of plant extracts, choice
of extraction methods and antimicrobial tests employed and on test microorganisms
(Nostro et al., 2000 and Hammer et al., 1999). The beneficial medicinal effect of plant
materials basically results from the secondary products present in the plant and is not
usually attributed to a single compound but a combination of the metabolites (Parekh et
al., 2005). Because of available antimicrobials failure to treat infectious diseases, many
researchers have focused on the investigation of natural products as source of new
bioactive molecules. A variety of methods are found for this purpose and since not all of
them are based on same principles, results obtained will also be profoundly influenced not
only by the method selected, but also by the microorganisms used to carry out the test, and
by the degree of solubility of each test compound. The test systems should ideally be
simple, rapid, reproducible, inexpensive and maximize high sample throughput in order to
cope with a varied number of extracts and fractions. The complexity of the bioassay must
be defined by laboratory facilities and quality available personnel. The currently available
screening methods for the detection of antimicrobial activity of natural products fall into
three groups, including bioautographic, diffusion, and dilution methods. The
bioautographic and diffusion methods are known as qualitative techniques since these
methods will only give an idea of the presence or absence of substances with antimicrobial
activity. On the other hand, dilution methods are considered quantitative assays once they
determine the minimal inhibitory concentration. Antimicrobial activities reported in the
literature have been evaluated with diverse sets of methodologies, degrees of sensitivity,
17
amount of test compounds and microbial strains, often difficult to compare (Cowan,
1999).
Plants with antihelmintic activity
The World Health Organization estimates that a staggering two billion people
harbor parasitic worm infections. Parasitic worms also infect livestock and crops, affecting
food production with a resultant economic impact. Despite this prevalence of parasitic
infections, the research on anthelmintic drug is poor. As per WHO, only few drugs are
frequently used in the treatment of helminthes in human beings. Anthelmintics from the
natural sources may play a key role in the treatment of these parasite infections (Aswar
Manoj et al., 2008). Helminth infections are among the most common infections in
humans, affecting a large population of the world. Although the majority of infections due
to worms are generally limited to tropical regions and pose a great threat to health and
contribute to the prevalence of malnutrition, anaemia, eosinophilia and pneumonia
(Bundy, 1994). Parasitic diseases cause severe morbidity affecting mainly population in
endemic areas with major economic and social consequences (Tagbota and Townson,
2001). The gastro-intestinal helminthes becomes resistant to currently available
antihelmintic drugs therefore there is a foremost problem in treatment of helminthes
diseases (Sondhi et al., 1994), hence there is an increasing demand towards natural
antihelmintics.
Parasitic worms also infect livestock and crops, affecting food production with a
resultant economic impact. Also of importance is the infection of domestic pets. Indeed,
the animal market is a major economic consideration for animal health, thus companies
are undertaking drug discovery programmes. Despite the prevalence of parasitic worms,
anthelmintic drug discovery is poor in relation of the pharmaceutical industry. The simple
reason is that the nations which suffer most from these tropical diseases have little money
to invest in drug discovery or therapy. It comes as no surprise therefore that the drugs
available for human treatment were first developed as veterinary medicines. There is thus
a pitifully small repertoire of chemotherapeutic agents available for treatment. In some
respects, this situation has been exacerbated by the remarkable success of ivermectin over
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the last twenty years (Geary, 2005), which has decreased motivation for anthelmintic drug
discovery programmes (Geary Patel et al., 1999). This prompts concern, as anthelmintic
resistance has been widely reported in livestock and it may also only be a matter of time
before this phenomenon occurs in parasites of humans.
Helminth infections are among the most common infections in man, affecting a
large proportion of population all over the world. In developing countries they pose a large
threat to public health and contribute to the prevalence of malnutrition, anaemia,
eosinophilia and pneumonia. Although the majority of infections caused due to worms are
generally limited to tropical regions. Parasitoses have been of concern to the medical field
for centuries and the helminthes still cause considerable problems for human beings and
animals. During the past few decades, despite numerous advances made in understanding
the mode of transmission and the treatment of these parasites, there are still no efficient
products to control certain helminths and the indiscriminate use of some drugs has
generated several cases of resistance. Furthermore, it has been recognized recently that
anthelmintic substances having considerable toxicity to human beings are present in foods
derived from livestock, posing a serious threat to human health (Patel et al., 2011). Some
workers have reported antihelmintic activity in the essential oils of Piper betle Linn.,
Anancardium occidentale Linn. and seed oils of Gynandropsis gynandra Linn., Impatiens
balsamina Linn., Celastrus peniculata Willd., Embelia ribes Burm. F. and Mucuna prurita
Hook. against the earthworm Pheretima Posthuma (Mali and Mehta, 2008).
Plants with potential anthelmintic activity (Behnke et al., 2008)
Species Enzymes known to be contained Papaya papain, chymopapain, caricain, glycyl endopeptidase Fig ficin, ficain Pineapple ananain, fruit bromelain, stem bromelain, comosain Kiwi fruit Actinidain Egyptian milkweed Asclepain Cowhage Mucunain
syndrome, glucagonoma, and drugs or chemical induced reactions (eg: glucocorticoids,
anticancer agents, streptozotocin or diazoxide, thiazide, some psychoactive agents).
Diagnosis of early Diabetes Mellitus in diabetes are hyperglycemia, glycosuria, loss of
weight due to increased breakdown of fat and tissue protein, increased production of
ketone bodies by liver and their incomplete utilization by the tissue leading to their
accumulation in blood (Ketosis) and elimination in urine (Ketonuria), lowering of PH of
blood due to circulating keto acids (acidosis), dehydration due to elimination of large
amounts of water with glucose in urine, increased levels of lipid, fatty acids and
cholesterol in blood (lipemia) and increased tendency to develop cataract in the eye and
atheromatous and artherosclerotic lesions of blood vessels (Wadkar et al., 2008).
25
Diabetes mellitus is a metabolic disorder of the endocrine system. The disease is found
in all parts of the world and is rapidly increasing worldwide. People suffering from
diabetes cannot produce or properly use insulin, so they have high blood glucose. Type 2
diabetes, non–insulin-dependent diabetes mellitus, in which the body does not produce
enough insulin or properly use it, is the most common form of the disease, accounting for
90%–95% of cases. Type 2 is nearing epidemic proportions as a result of an increased
number of elderly people and a greater prevalence of obesity and sedentary lifestyle. The
cause of diabetes is a mystery, although both genetic and environmental factors such as
obesity and lack of exercise appear to play a role. According to World Health
Organization projections, the diabetic population is likely to increase to 300 million or
more by the year 2025. Currently available therapies for diabetes include insulin and
various oral antidiabetic agents such as sulfonylureas, biguanides, a-glucosidase
inhibitors, and glinides, which are used as monotherapy or in combination to achieve
better glycemic regulation. Many of these oral antidiabetic agents have a number of
serious adverse effects; thus, managing diabetes without any side effects is still a
challenge. Therefore, the search for more effective and safer hypoglycemic agents has
continued to be an important area of investigation. The hypoglycemic effect of several
plants used as antidiabetic remedies has been confirmed, and the mechanisms of
hypoglycemic activity of these plants are being studied. New natural products reported
from 2001 to 2004 with antidiabetic potential that have potent medicinal activities with
diverse structures (Jung et al., 2006).
Diabetes mellitus is a disease in which blood vessels of glucose (sugar) are high
because the body does not produce or properly use insulin. There are two major forms of
diabetes mellitus. Type 1 diabetes develops when the pancreas does not produce insulin.
Type 2 diabetes occurs when the body cell resist insulin’s effect (Microsoft Encarta,
2009). This condition leads to elevated levels of blood glucose. The normal range of blood
glucose level for blood glucose level is between 70-110mg/dl. Insulin is a hormone that
helps to maintain normal blood glucose level by making the body’s cell absorbs glucose
(sugar) so that it can be as a source of energy. In people with diabetes glucose levels build
26
up in the blood and urine causing excessive urination, thirst, hunger and problems with
fats and protein metabolism because the body cannot convert glucose into energy, it
begins to break down stored fats for fuel. This produces increasing amounts of acidic
compounds in the blood called ketone bodies which interfere with cellular respiration
energy producing process in cells. Alloxan induces diabetes mellitus in rats. Alloxan, a
beta cytotoxin, induces diabetes in a wide variety of animal species through damage of
insulin secreting cell. These animals develop characteristic similar to type 1 diabetes in
humans. Hypercholesterolemia and hypertriglyceridemia are common complications of
diabetes mellitus (Rerup, 1999).
Coopertein and Watkins (1978), Lazarow (1964) have shown that alloxan probably
exerts toxic effect on the beta-cells by selectively interacting with certain components of
the plasma membrane. This results in an altered permeability which permits the diffusion
of extra cellular fluid markers such as D-mannitol and insulin into the surrounding
incubation medium. However, the fact that only beta-cell components of intermediate cells
are affected by alloxan suggests that there is no comparable damage to their plasma
membrane as occurs in the beta-cell (Cooperstein, 1964), but is consistent with the
possibility that alloxan interacts with the membranes of the beta-cell cytoplasmic
organelle. In intermediate cells this imitates the remarkably selective recognition and an
autophary of these organelles. The same considerations probably apply to the effects of
streptozotoxia on the intermediate cells. Alloxan is known to induce diabetic renal
changes as well as causing nephrotoxic alterations however. No ultra structural study has
been performed to differentiate diabetic verses toxic effect of tubules and glomerulus
(Andrew et al, 1992).
Diabetes mellitus is a debilitating and often life-threatening disorder with
increasing incidence throughout the world. Diabetic complications arise partly from
glycosylation damage to structural and functional proteins and reflect chronic failure to
maintain blood glucose homeostasis. Other complications such as diabetic nephropathy,
diabetic retinopathy, diabetic neuropathy and diabetic cardiomyopathy prevail as a result
of hyperglycemia. A scientific investigation of traditional herbal remedies for diabetes
27
may provide valuable leads for the development of alternative drugs and strategies.
Alternatives are clearly needed for better management of diabetes because of high cost
and poor availability of current therapies for many rural populations, particularly in
developing countries. Diabetic nephropathy is one of the microvascular complications of
diabetes. The pathophysiology involves an interaction between metabolic and
hemodynamic factors. Metabolic factors include advanced glycation, increased formation
of polyols and activation of protein kinase-C. Hemodynamic factors include systemic
hypertension, intraglomerular hypertension and the role of vasoactive hormones, such as
anglotensin II. Clinical course progresses from microalbuminuria to overt proteinuria and
then to renal failure. The field of herbal medicines research has been gaining significant
importance in the last few decades and the demand to use natural products in the treatment
of diabetes is increasing worldwide. The available literature shows that there are more
than 400 plant species showing antidiabetic activity. Although some of these plants have
great reputation in Ayurveda, the indigenous Indian system of medicine, many remain to
be scientifically established (Rao and Nammi, 2006). Diabetes mellitus is one of the
common metabolic disorders and 1.3% of the population suffers from this disease
throughout the world. Insulin and oral hypoglycemic agents like sulphonylureas and
biguanides are still the major players in the management of the disease. Due to lack of
insulin, hyperglycemia and glycosuria almost invariably occur. The search for a curative
agent against this disease resulted in the introduction of several hypoglycemic agents.
Some of which are used therapeutically. However, various harmful side effects and weak
effectiveness of them made their use limited and the search to find more effective agents
continues. Investigation in the plant kingdom culminated in the discovery of many herbal
hypoglycemic agents (Tatiya et al., 2011).
Traditional medicines from readily available medicinal plants offer great potential for
the discovery of new antidiabetic drugs. Many traditional plant treatments for diabetes
exist, a hidden wealth of potentially useful natural products for diabetes control.
Nonetheless, few traditional antidiabetic plants have received scientific or medical
scrutiny, despite recommendations by the World Health Organization in 1980 that this
should be undertaken. Medicinal plants that are the most effective and the most commonly
28
studied in relation to diabetes and its complications are: Gentiana olivieri griseb
(Gentianaceae), Bauhinia forficata koeingii (Leguminosae), Eugenia jambolana L.
(Myrtaceae), Lactuca indica L. (Compositae), Mucuna pruriens Bak. (Leguminosae),
Tinospora cordifolia W. (Menispermaceae), Momordica charantia L. (Cucurbitaceae),
Aporosa lindleyana Baill (Euphorbiaceae), Cogent db, Myrtus communis L. (Myrtaceae),
Rhizoma Polygonati Odorati (Liliaceae), and Terminalia pallida Brand. (Combretaceae).
Most of these plants have shown varying degrees of hypoglycemic and anti-
hyperglycemic activity. Among active medicinal herbs, Momordica charantia L.
(Cucurbitaceae), Pterocarpus marsupium Roxb. (Leguminoceae), and Trigonella foenum
greacum L. (Leguminosae) have been reported to be beneficial for treatment of type 2
diabetes (Jung et al., 2006).
Some plants having hypoglycemic activity (Grover, 2002; Srinivasa, 2005)
Plant Plant Part Type of Test Sample Trigonella foenum-gracecum seed Alcohol ,water extract Nephoelepsis tuberose bulb juice Costus specious rhizome juice Plantago ovata husk Powder Allium sativum bulb juice Hemidesmus indicus root alcoholic extract Allium cepa bulb juice
Plants with anticancer activity
Cancer, a major public health problem worldwide, is a group of diseases
characterized by uncontrolled growth and spread of abnormal cells. It affects all people,
the young and old, the rich and poor, men, women and children. Cancer is one of the
leading causes of death in the world and its incidence is still increasing, particularly in
developing countries. It is the second leading cause of death in developed countries, and is
among the three leading causes of death for adults in developing countries (Parkin et al.,
2001). External factors such as tobacco, chemicals, radiation, infectious organisms and
internal factors such as inherited mutations, hormones and immune status can be able to
cause cancer. These risk factors may act together or in sequence to initiate or promote
carcinogenesis (American Cancer Society, 2005). Many different types of chemical
29
exposures can increase the incidence of tumors in humans (Wogan et al., 2004). The only
types of radiation proven to cause human cancer are high-frequency ionizing radiation and
ultraviolet radiation. Exposure to sunlight causes almost all cases of basal and squamous
cell skin cancer and is a major cause of skin melanoma (Moan et al., 2008). Cancers
triggered by infections are more prevalent in the developing world. Both DNA and RNA
viruses were documented as a causative factor of experimental carcinogenesis (Shillitoe,
1991). More than 100 oncogenes have been identified to date, and many among them have
been implicated in carcinogenesis, including ras, c-myc, erb-B2 and epidermal growth
factor receptor (Duesberg and Liu, 2003; Carbone and Pass, 2004). Cancer can be treated
by surgery, radiation therapy, chemotherapy and immunotherapy. Cancers that are most
often cured are breast, cervix, prostate, oral, colon and skin, if they are diagnosed early.
Improving the quality of life of patients living with cancer and dying from cancer is
therefore an urgent humanitarian need. Indian sub-continent is rich in its diversity of flora,
being a tropical country with a large spread of rain forests and river basins. It is
floristically rich with about 33 percent of its botanical wealth (over 15,000 species of
higher plants) being endemic. Numerous bioactive compounds have been isolated from
plant sources and several of them are currently in clinical trials. Plant-derived compounds
have been a vital source of varied clinically useful anti-cancer agents: Camptothecin
derivatives (Kepler et al., 1969), Topotecan and Irinotecan, Etoposide, derived from
Epipodophyllotoxin (Utsugi et al., 1996), and Paclitaxel (taxol) (Cragg and Newman,
2005). Furthermore, other potent molecules include Vinca rosea alkaloids (Vinblastine,
Vincristine) (Johnson et al., 2001), Flavopiridol, a semi-synthetic analogue of the
chromone alkaloid and Rohitkine, a pyridoindole alkaloid derived from leaves of
Ochrosia species (Arguello et al., 1998). The research on anticancer drug development is
largely dependent on exploring potential phytochemicals.
Polycyclic aromatic hydrocarbons (PAHs) are products formed by incomplete
combustion of organic matter. Sources of PAHs include industrial and domestic oil
furnaces, gasoline, and diesel engines. PAHs are widely distributed in our environment
and are implicated in various types of cancer. Enzymatic activation of PAH’s leads to the
generation of active oxygen species such as peroxides and superoxide anion radicals,
30
which induce oxidative stress in the form of lipid peroxidation. The PAH 7,12-dimethyl-
benz(a)anthracene (DMBA) acts as a potent carcinogen by generating various reactive
metabolic intermediates leading to oxidative stress. It is therefore imperative to search
alternative drugs for the treatment of liver disease to replace the currently used drugs of
doubtful efficacy and safety (Bishayee et al., 2000). Most tumor initiating agents either
generate or are metabolically converted to electrophilic reactants which bind covalently to
cellular DNA (Slaga et al., 1987; DiGiovannio, 1992). For a number of PAH's, including
DMBA the ultimate carcinogen is so called Bay-region dihydrodiol epoxide, produced
during cellular metabolism (Harry, 2001). Free radicals and these modified DNA bases
have been strongly implicated in carcinogenesis in general (Floyd, 1990; Mollins, 1993).
A high correlation has been found to occur between the dose of administered DMBA and
the levels of total DNA adducts in liver and target organ epithelial cells. Presumably this
is due to the fact that liver cells have a greater capacity of metabolizing PAHs, as
compared with the target cells for tumorigenicity, which become more readily saturated
(Izzotti et al., 1999). DMBA is the most well known polycyclic aromatic hydrocarbon that
is used as a chemical inductor of model mammary carcinogenesis (Huggins et al., 1961).
The main advantage of using DMBA as chemical carcinogen in rodent model is that it
closely mimics human breast disease. Both of these cancers arise from ductal epithelial
cells. Histopathological characterization of DMBA-induced mammary hyperplastic,
premalignant and malignant lesions shows that rat mammary adenocarcinomas and the
most common human breast carcinomas share several histological and morphological
similarities (Costa et al., 2002).
Chemical carcinogen like DMBA binds with DNA which is considered to be
essential for its tumor inducing ability. Inhibitory effect of any chemopreventive agent
against DMBA induced tumorigenesis correlates with decreased binding of DMBA to
DNA. Cell proliferation has important role in carcinogenesis as cancer proceeds through
inactivation of negative regulators of cell proliferation and activation of positive regulators
of cell proliferation (Coleman and Tsongalis, 2006). Toxic manifestation of DMBA is
associated with its oxidative metabolism leading to the formation of reactive metabolites
(epoxides and quinines) capable of generating free radicals. Metabolism of PAHs like
31
7,12-dimethyl benz(a)anthracene by the mixed function oxidases system (MFO) often
results in the formation of oxy-radicals “O2−, 1O2, H2O2, OH,” which bind covalently to
nucleophillic sites on cellular macromolecules thereby eliciting cancerous responses (Giri
et al., 1995). Oxidative stress induced due to the generation of free radicals and/or
decreased antioxidant level in the target cells and tissues has been suggested to play an
important role in carcinogenesis (Huang et al., 1999). Increased incidence of oxidative
stress and lipid peroxidation are implicated in carcinogenic processes (Khanzode
Khanzode 2004).
Cancer cachexia is a common clinical problem that substantially impacts upon the
quality of life and survival of cancer patients. The pathophysiology of this syndrome
implicates tumour induced metabolic changes and immune response. Clinical
manifestations include anorexia, chronic nausea and change in body image. (Nayak,
2002). Vinblastine isolated from the Catharanthus rosesus (Farnsworth and Blowster,
1967) is used for the treatment of Hodgkins, choriocarcinoma, non-hodgkins lymphomas,
leukemia in children, testicular and neck cancer. Vincristine is recommended for acute
lymphocytic leukemia in childhood advanced stages of hodgkins, lymophosarcoma, small
cell lung, cervical and breast cancer (Farnsworth and Bingel, 1977). Among several
potential benefits of ayurvedic medicine, relief from cancer cachexia is the most valuable.
Herbs used in cancer therapy provide not only total healing, but also reduces the side
effects and cancer associated complications. It also avoids the need for supplemental
therapy to manage cancer. Each herbal product contains multiple active principles that
may operate synergistically, producing therapeutic benefits and lowering the risks on
adverse effects. The anorexia or weight loss could be effectively managed by Withania