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Natural products for cancer prevention: a global perspective
L. Reddy
a
, B. Odhav
a
, K.D. Bhoola
b,
*
a
Department of Biotechnology, Durban Institute of Technology, P.O. Box 1334, Durban 4000, South Africa
b
Asthma and Allergy Research Institute, University of Western Australia, Ground Floor, E Block, Sir Charles Gairdner Hospital,
Hospital Avenue, Nedlands, WA 6009, Australia
Abstract
The control of cancer, the second leading cause of death worldwide, may benefit from the potential that resides in alternative therapies.
The primary carcinogens stem from a variety of agricultural, industrial, and dietary factors. Conventional therapies cause serious side effects
and, at best, merely extend the patient’s lifespan by a few years. There is thus the need to utilise alternative concepts or approaches to the
prevention of cancer. This review focuses on the many natural products that have been implicated in cancer prevention and that promote
human health without recognisable side effects. These molecules originate from vegetables, fruits, plant extracts, and herbs.
D2003 Elsevier Science Inc. All rights reserved.
Keywords: Cancer prevention; Natural products; Plants; Anticancer; Chemoprotection
Abbreviations: BBI, bisbenzylisoalkaloids; IC
50
, fifty percent inhibitory concentration; i.p., intra-peritoneal.
Contents
1. Introduction ............................................. 1
2. Cancer................................................ 2
2.1. Carcinogens ......................................... 2
2.2. Cell cycle .......................................... 2
2.3. Carcinogenesis ........................................ 3
2.4. Global cancer incidence ................................... 3
3. Epidemiological studies ....................................... 3
4. Natural products and defense against carcinogenesis ........................ 4
5. Mechanisms of action of natural products on carcinogenesis .................... 6
5.1. Antioxidants ......................................... 7
5.2. Fatty acids .......................................... 8
5.3. Amino acids and related compounds ............................ 8
5.4. Flavonoids .......................................... 9
5.5. Resveratrol.......................................... 9
5.6. Alkaloids .......................................... 10
5.7. Semisynthetic anticancer drugs ............................... 10
6. Summary .............................................. 10
Acknowledgments ............................................ 11
References ................................................ 11
1. Introduction
Mortality that results from the common forms of cancer
is still unacceptably high. Despite many therapeutic advan-
0163-7258/03/$ – see front matter D2003 Elsevier Science Inc. All rights reserved.
doi:10.1016/S0163-7258(03)00042-1
* Corresponding author. Tel.: +61-8-9346-2954; fax: +61-8-9346-
2816.
E-mail address: Bhoolakd@yahoo.com (K.D. Bhoola).
www.elsevier.com/locate/pharmthera
Pharmacology & Therapeutics 99 (2003) 1 – 13
ces in the understanding of the processes in carcinogenesis,
overall mortality statistics are unlikely to change until there
is a reorientation of the concepts for the use of natural
products as new chemopreventive agents. Natural or semi-
synthetic compounds may be used to block, reverse, or
prevent the development of invasive cancers. Cellular car-
cinogenesis forms the biologic basis for the identification of
preventive products, the assessment of their activity, and
ultimately the success or failure of a therapy.
As long ago as 480 BC, Hippocrates recognised that
several aspects of what we now call ‘‘lifestyle’’ must come
together to produce a healthy body. He said, ‘‘Positive
health requires a knowledge of man’s primary constitution
and the powers of various foods, both those natural to them
and those resulting from human skill.’’ What Hippocrates
called ‘‘man’s primary constitution,’’ we today call ‘‘gen-
etics,’’ and we can infer that foods ‘‘resulting from human
skills’’ can be equated with today’s diet.
Cancers may be caused in one of three ways, namely
incorrect diet, genetic predisposition, and via the envir-
onment. At least 35% of all cancers worldwide are caused
by an incorrect diet, and in the case of colon cancer, diet
may account for 80% of the cases. When one adds alcohol
and cigarettes to their diet, the percentage may increase to
60%. Genetic predisposition to cancer lends itself to 20%
of cancer cases, thus leaving the majority of cancers being
associated with a host of environmental carcinogens. Doll
and Peto (1981) reported that in the United States the major
environmental carcinogens include air and water pollution,
radiation, and medication.
2. Cancer
2.1. Carcinogens
The majority of human cancers result from exposure to
environmental carcinogens; these include both natural and
manmade chemicals, radiation, and viruses. Carcinogens
may be divided into several classes, as shown in Table 1.
(1) Genotoxic carcinogens, if they react with nucleic acids.
These can be directly acting or primary carcinogens, if they
are of such reactivity so as to directly affect cellular
constituents. (2) Alternatively, they may be procarcinogens
that require metabolic activation to induce carcinogenesis.
(3) Epigenetic carcinogens are those that are not genotoxic.
Molecular diversity of the cancer-initiating compounds
ranges from metals to complex organic chemicals (Fig. 1),
and there is large variation in potency. The variation in
structure and potency suggests that more than one mech-
anism is involved in carcinogenesis.
It is also clear that apart from exposure to carcinogens
other factors such as the genetic predisposition have been
documented. Thus, patients with the genetic xeroderma
pigmentosum are more susceptible to skin cancer. Fur-
thermore, incidence of bladder cancer is significantly
higher in those individuals who have the slow acetylator
phenotype, especially if they are exposed to aromatic
amines.
Carcinogens in the diet that trigger the initial stage
include moulds and aflatoxins (for example, in peanuts
and maize), nitrosamines (in smoked meats and other cured
products), rancid fats and cooking oils, alcohol, and addi-
tives and preservatives. A combination of foods may have a
cumulative effect, and when incorrect diet is added to a
polluted environment, smoking, UV radiation, free radicals,
lack of exercise, and stress, the stage is set for DNA damage
and cancer progression. On the protective side, we know
that a diet rich in fruit, vegetables, and fibre is associated
with a reduced risk of cancer at most sites.
2.2. Cell cycle
Cancer is a disease in which disorder occurs in the
normal processes of cell division, which are controlled by
the genetic material (DNA) of the cell. Viruses, chemical
carcinogens, chromosomal rearrangement, tumor sup-
pressor genes, or spontaneous transformation have been
implicated in the cause of cancer. For a cell to replicate, it
must (1) faithfully reproduce its DNA, (2) manufacture
sufficient cellular organelles, membranes, soluble proteins,
etc., to enable the daughter cells to survive, and (3)
partition the DNA and cytoplasm (containing organelles)
equally to form two daughter cells. This process requires a
significant amount of feedback control to ensure that the
molecular steps are sequential and correctly orientated.
Failure to control the cell cycle process carries with it a
high price. Higher eukaryotes have a ‘‘dead man’s handle’’
safety system, whereby their basic life program undergoes
apoptosis.
Table 1
Types of carcinogens (Timbrell, 2000)
Type Example
1. Genotoxic carcinogen
Primary, direct-acting alkylating
agents
Dimethylsulfate, ethylene imine,
b-propiolactonel
2. Procarcinogens
Polycyclic aromatic hydrocarbons Benzo[a]pyrene
Nitrosamines Dimethylnitrosamine
Hydrazine 1,2-Dimethylhydrazine
Inorganic Cadmium, plutonium
3. Epigenetic carcinogens
Promotors Phorbol esters, saccharin, bile acids
Solid state Asbestos, plastic
Hormones Estrogens
Immunosuppressants Purine analogues
Cocarcinogens Catechol
4. Unclassified
Peroxisome proliferators Clofibrate, phthalate esters
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–132
2.3. Carcinogenesis
The transformation of a normal cell into a cancerous
cell is believed to proceed through many stages over a
number of years or even decades. The stages of carcino-
genesis include initiation, promotion, and progression. The
first stage involves a reaction between the cancer-pro-
ducing substance (carcinogen) and the DNA of tissue
cells. There may be a genetic susceptibility. This stage
may remain dormant, and the subject may only be at risk
for developing cancer at a later stage. The second stage
occurs very slowly over a period ranging from several
months to years. During this stage, a change in diet and
lifestyle can have a beneficial effect so that the person may
not develop cancer during his or her lifetime. The third
and final stage involves progression and spread of the
cancer, at which point diet may have less of an impact.
Preventing initiation is an important anticancer strategy, as
are the opportunities to inhibit cancer throughout the latter
stages of malignancy.
One of the most important mechanisms contributing to
cancer is considered to be oxidative damage to the DNA. If a
cell containing damaged DNA divides before the DNA can be
repaired, the result is likely to be a permanent genetic
alteration constituting a first step in carcinogenesis. Body
cells that divide rapidly are more susceptible to carcino-
genesis because there is less opportunity for DNA repair
before cell division. Mutagenic changes in the components of
signalling pathways lead to cellular transformation (cancer).
2.4. Global cancer incidence
Modern man is confronted with an increasing incidence
of cancer and cancer deaths annually. Statistics indicate that
men are largely plagued by lung, colon, rectum, and
prostrate cancer, whilst women increasingly suffer from
breast, colon, rectum, and stomach cancer (Abdulla &
Gruber, 2000).
3. Epidemiological studies
A recent United States study was conducted involving
628 men under the age of 65 years with newly diagnosed
prostrate cancer. They were placed on a trial of fruit and
vegetables for 5 years. It was found that while fruit was not
protective, vegetables, especially cruciferous vegetables
(cabbage, broccoli, brussel sprouts, and cauliflower),
reduced risk. Tomatoes containing lycopene are protective
against prostrate cancer, and when a-tocopherol (a variety
of vitamin E) is added to lycopene, prostrate cancer pro-
gression may be curtailed by almost 90% (Klein et al.,
2001). Other research has found that plant sterols and
sterolins found in pumpkinseeds, the African potato, and
some vegetables have a beneficial effect on prostrate health.
A large study involving 35,000 nonsmoking, mainly
vegetarian, Seventh Day Adventists found a reduced risk
of lung, prostrate, pancreas, and colon cancers. Antioxidant
vitamins also help to fight the damage caused by harmful
stomach bacteria and are protective (Pryor et al., 2000). The
low incidence of large bowel cancers in India can be
attributed to their diet high in carbohydrates and natural
antioxidants, including turmeric. Animal studies have
shown that squalene, found in olive oil, inhibits colon, lung,
and skin cancers. A Japanese study found that the probiotic
Lactobacillus (found in yogurt) can delay the onset of
cancer by enhancing the activity of natural killer cells,
which are the particular white blood cells responsible for
attacking foreign invaders.
Women in Japan and the Far East have a much lower
incidence of breast cancer than women in the West. These
women have a high consumption of soy products containing
isoflavones, which are phytoestrogen or plant estrogen.
Phytoestrogens bind the estrogen receptors in the body
and therefore block the cancer-promoting effects of estro-
gen. Researchers from the University of Texas supple-
mented the diet of women with isoflavones contained in
soymilk, and this reduced estrogen levels by 25% and
progesterone levels by 45%. Plant estrogens are also found
in red clover, black cohosh, rhubarb, and flaxseed and are
highly recommended to reduce breast and prostrate cancer
(Demark-Wahnefried et al., 2001).
The changing profiles in the incidence of certain cancers
in South Africa has been attributed to urbanisation, with
increased consumption of meat, refined carbohydrates, alco-
hol, and smoking. The rural African diet of samp, beans,
and vegetables was a perfect combination of protein and
complex carbohydrates with adequate fibre and plant
nutrients. This has given way to white bread, jam, soft
drinks, and fast foods. The cause of esophageal cancer, so
Fig. 1. Structures of various carcinogens (Timbrell, 2000).
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–13 3
common in the Transkei, has eluded scientists for decades. It
has been postulated that possible causes could be aflatoxins
(toxins manufactured by detrimental fungi that often grow
on foods) found in maize or a mineral deficiency in the soil.
Another carcinogenic chemical is dioxin, which enters the
food chain when animals eat contaminated plants. When
humans consume meat, dairy products, and fish, they ingest
a highly concentrated load of dioxin, which has been linked
to several cancers. A recent study indicated that woman who
ate healthy diets were 30% less likely to die than those who
did not. South African blacks have a lower incidence of
colon cancer than whites, which was found to be due to a
lower intake of animal protein and fat (O’Keefe et al.,
1999). Epidemiological studies involving various human
cancer sites indicate that fruit and vegetable intake signific-
antly protects against cancer (Table 2).
4. Natural products and defense against carcinogenesis
The literature indicates that many natural products are
available as chemoprotective agents against commonly
occurring cancers occurring worldwide. A major group of
these products are the powerful antioxidants, others are
phenolic in nature, and the remainder includes reactive
groups that confer protective properties. These natural
products are found in vegetables, fruits (Table 3), plant
extracts, and herbs (Table 4). Although the mechanism of
the protective effect is unclear, the fact that the consumption
of fruit and vegetables lowers the incidence of carcino-
genesis at a wide variety of sites is broadly supported. The
epidemiological evidence suggests protection against a wide
array of cancers (Table 2), particularly those of the respir-
Table 2
Epidemiological studies of fruit and vegetable intake and cancer prevention
Cancer site Number
of studies
Significant
protective
effects
Significantly
increased
risk
All sites including prostate 170 132 6
All sites except prostate 156 128 4
Lung 25 24 0
Larynx 4 4 0
Oral cavity, pharynx 9 9 0
Esophagus 16 15 0
Stomach 19 17 1
Colorectal 27 20 3
Bladder 5 3 0
Pancreas 11 9 0
Cervix 8 7 0
Ovary 4 3 0
Breast 14 8 0
Prostrate 14 4 2
Miscellaneous
1
860
1
Melanoma, thyroid, biliary tract, mesothelioma, endometrial, and
childhood brain tumors (Langset, 1995).
Table 3
Chemoprotective antioxidants from fruits vegetables
Source Active component Mechanism of action Cancer inhibited (reference)
Olives Polyphenols Antioxidant Various cancers (Langset, 1995)
Apples Antioxidant Various cancers (Eberhardt et al., 2000)
Strawberries,
cantaloupe, melon
Vitamin C, bioflavonoids,
chalcones
Antioxidant Various cancers (Paiva & Russell, 1999)
Leafy greens, cabbage,
broccoli, cauliflower
Vitamin C, lutein and
zeaxanthin
Scavenger of ROS, antioxidant,
suppresses promotion of lung
tumors in mice
Various cancers; crypt foci in SD rat colon
(Abdulla & Gruber, 2000; Ceruti et al., 1986;
Nishino et al., 2000; Rauscher et al., 1998;
Stahl et al., 2000)
Vegetables oils, cold-
pressed seed oils,
wheat germ
Vitamin E Protects against lipid peroxidation Skin cancer (Paiva & Russell, 1999;
Stahl et al., 2000)
Yellow-orange
vegetables and fruits
b-Carotene Antioxidant Various cancers (Paiva & Russell, 1999;
Stahl et al., 2000)
Carrots a- and b-carotene,
phenolic compounds
Antioxidant, pS2 gene expression,
a-carotene more effective, inhibits
tumors in rats and mice
Pancreatic, colon, breast cancer; liver cells; rat,
mice colon and liver cancer (Cheng et al., 2001;
Eberhardt et al., 2000; King et al., 1997; Nishino
et al., 2000)
Tomatoes Lycopene, vitamin C Strong antioxidant, inhibits
lymphocyte DNA-oxidated damage
Leukemia, lung cancer; mice tumors
(Giovannucci, 1999; Hecht et al., 1999; Kim
et al., 2000a; Watzl et al., 1999)
Grapes, red wine Phenols, catechins Antioxidant Various cancers (Abdulla & Gruber, 2000)
Citrus fruits b-Cryptoxanthin,
bioflavonoids, chalcones,
vitamin C
Antioxidant, stimulates expression
of RB gene and p73 gene
(a p53-related gene)
Rat tumors; various cancers (Nishino et al., 2000)
Garlic, onions, leeks,
chives
Allicin, flavonoids,
vitamin C, selenium,
sulfur
Detoxifies carcinogen, inhibits
Helicobacter pylori, cell cycle
arrest from S to G2M boundary phase
Stomach cancer (Barch et al., 1996;
Zheng et al., 1997)
Common bean Phenolic compounds Antimutagenic Aflatoxin-induced cancer (Cardador-Martinez
et al., 2002; Galvano et al., 2001)
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–134
atory and digestive tracts and to a lesser extent the hormone-
related cancers. A host of plant constituents could be
responsible for the protective effects, and it is likely that
several of them play a role under some circumstances. Most
of the nonnutrient antioxidants in these foods are phenolic
or polyphenolic compounds, such as isoflavones in soy-
beans, catechins in tea, phenolic esters in coffee, phenolic
acid in red wine, quercetin in onions, and rosmaric acid in
rosemary.
Of the many anticarcinogens already detected in plant
foods, the antioxidants vitamins C and E and the provitamin
b-carotene have received the most attention (Handelman,
2001). Although there has been considered enthusiasm for
the potential anticarcinogenic properties of b-carotene,
Table 4
Chemoprotective products found in plant extracts causing molecular changes
Source Active component Mechanism of action Cancer inhibited (reference)
Gymnosporia rothiana Laws GCE: chloroform ether
extract
DNA/RNA and protein synthesis
inhibited after treatment for 12 – 36 hr
Leukemia in mice (Chapekar &
Sahasrabudhe, 1981)
Rhizoma zedoariae b-Elemene Cell cycle arrest from S to G2M phase (Yuan et al., 1999; Zheng et al., 1997)
Pinus pinaster,P. maritime Polyphenolic fraction,
ferrulic acid, bioflavonoids,
proanthocyanidins Procydin
(SA), Pycnogenol (Europe)
Antioxidant, improves blood
circulation, increases cytokine levels,
increases activity of NK cells,
modulates mitogenic signaling and
induction of G1 arrest and apoptosis
DU145 cells, prostrate, skin cancer
(Agarwal et al., 2000)
Viscum album var., Viscum
var. coloratum (Korean
mistletoe)
Lectin alkaloids Caspase-3 activation, lectin 11-induced
apoptosis, inhibition of telomerase via
mitochondrial controlled pathway
independent of p53, enhancement of
cytokine release
U937, HL-60, lymphoblastoid cells,
hepatocarcinoma cells (Duong Van Huyen
et al., 2001; Kim et al., 2000b; Lyu et al.,
2001; Park et al., 2001; Ribereau-Gayon
et al., 1997)
Hexamethylene bioacetamide p53-dependent apoptosis, induction
with telomerase activity
Human colon carcinoma LoVo cells,
leukemic cells (Zhang et al., 2000)
Azadirachta indica Juss
(Neem leaf)
Polyphenolic Cytotoxic Various cancers (Gogate, 1991)
Muscadene berries Resveratrol Antioxidant Lung tumor in A/J mice (Hecht et al., 1999)
myo-Inositol, dexamethasone Antioxidant Lung tumor in A/J mice, liver cancer
(Hecht et al., 1999; Witschi et al., 1999)
Curcuma longa L. turmeric Curcumin Antioxidant Prostate, lung tumor in A/J mice
(Dorai et al., 2001; Hecht et al., 1999; Li &
Lin-Shia, 2001)
Esculetin Antioxidant Lung tumor in A/J mice (Hecht et al., 1999)
Acanthopanax gracilistylus
(Chinese herb)
Antioxidant Liver cancer cells (Lin & Huang, 2000)
Cylopia intermedia
(honeybush tea)
Polyphenolic compounds Antioxidant, antimutagenic, interferes
with P450-mediated metabolism
Various cancers (Marnewick et al., 2000)
Undaria pinnantifida
(seaweed)
(Viva-Natural) Prophylactic Lewis lung cancer in mice (Furusawa &
Furusawa, 1985)
Rosemary, sage, other spices Carnosic acid, rosemary acid
Rubia cordifolia RC-18 Forms DNA adducts P388 and L1210 cells, B16 melanoma
(Adwankar & Chitnis, 1982; Poginsky
et al., 1991)
Valepotriates Cytotoxic (Bounthnah et al., 1981)
Scutellariae radix,S. indica Flavonoids Prostaglandin E
2
production Rat C6 glioma cells (Nakahata et al., 1998)
Soybeans Isoflavones, phenolic acids,
genistein (piperazine
complex)
Protein tyrosine kinase inhibitor, diverse
EGFR and p21 ras expression
phenotypes, dependent on epidermal
cell growth factor receptor,
estrogen-like action
Jurkat T-leukemia cells, bladder cancer
(Abdulla & Gruber, 2000; Polkowski &
Mazurek, 2000; Spinozzi et al., 1994;
Theodorescu et al., 1998)
Various plants Quercetin, kaempferol, rutin,
hesperidin
OH scavenger B16 melanoma (Day et al., 2000;
Drewa et al., 2001)
Camellia sinensis, green tea,
black tea
Polyphenols,
epigallocatechin-3-gallate
Apoptosis induction, cell cycle arrest Tumor cells (Ahmad et al., 1997;
Zhao et al., 1997)
Apalathus linearis
(unfermented rooibos tea)
Coriolus versicolor
(Chinese herb)
Bis-benzylisoalkaloids,
bufalin, berberine, tetrandrine
Apoptosis induction, complexes
with DNA
HL-60, U937 cells (Dong et al., 1997;
Jing et al., 1994; Kuo et al., 1995)
Uncaria tomentosa Apoptosis induction Tumor cells (Sheng et al., 1998)
Eucalyptus grandis Euglobal-G1 Various cancers (Takasaki et al., 2000)
Ornithogalum Cholestane glycoside Apoptosis induction HL-60 cells (Hirano et al., 1996)
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–13 5
research findings suggest that several different carotenoids
are likely to be associated with reduced cancer risks. In two
intervention trials to investigate the potential protective
effects of b-carotene against cancer, an unexpected signific-
antly higher incidence of lung cancer was found in men
taking supplements compared with those not taking addi-
tional b-carotene. These men were long-time heavy smokers
and may represent a special case in that their lung cancer
may have been initiated many years before the study took
place (Michaud et al., 2000). These results cause concern
and need serious consideration. They do not invalidate the
concept of the importance of antioxidant nutrients but do
underline the need to examine the relative influence of
supplements of a single antioxidant nutrient (as distinct
from complex mixtures of antioxidants in foods) as well
as interactions between the effects of smoking, antioxidant
nutrients, and disease progression.
A number of naturally occurring compounds from veg-
etables and herbs exert chemopreventive properties against
carcinogenesis. Most studies appear to test the natural
products on human leukemia cells. The Chinese medicinal
herb Rhizoma zedoariae, for example, produces a com-
pound called lemene, which has been shown to exhibit
antitumor activity in human and murine tumor cells in vitro
and in vivo (Zheng et al., 1997). The IC
50
values of lemene
indicated severe inhibition of promyelocytic HL-60 cells,
erythroleukemia K562 cells, and especially peripheral blood
leukocytes. This was associated with cell arrest from S to
G2M phase transition and with induction of apoptosis (Yuan
et al., 1999). Similar inhibitory effects were produced by
allicin, a natural organosulfide from garlic. In vitro inhibi-
tion of proliferation of HL-60 cells or induction of apoptosis
in promyelocytic leukemia was also demonstrated by Dong
et al. (1997) using other Chinese medicinal products,
namely the bis-benzylisoquinoline alkaloids, tetrandrine
and berberine, by Jing et al. (1994) using bufalin, by Sheng
et al. (1998) using extracts of Uncaria tomentosa, and by
Hirano et al. (1996) using cholestane glycosidase.
5. Mechanisms of action of
natural products on carcinogenesis
In the last decade, advances in cancer research have
enhanced our understanding of cancer biology and genetics.
Among the most important of these is that the genes that
control apoptosis have a major effect on malignancy
through the disruption of the apoptotic process that leads
to tumor initiation, progression, and metastasis. Therefore,
one mechanism of tumor suppression by natural products
may be to induce apoptosis (Table 4), thereby providing a
genetic basis for cancer therapy by natural products.
The p53 protein, encoded by a tumor suppressor gene,
mediates growth arrest or apoptosis in response to a variety
of stresses. p53-Dependent apoptosis, occurring in several
sensitive tissues after radiation or chemotherapy, is partially
responsible for the side effects of cancer treatment, making
p53 a potential target for therapeutic suppression. Hypoxic
stress, such as DNA damage, induces p53 protein accu-
mulation and p53-dependent apoptosis in oncogenically
transformed cells. Unlike DNA damage, hypoxia does not
induce p53-dependent cell cycle arrest, suggesting that p53
activity is differentially regulated by these two stresses.
Genotoxic stress induces both kinds of interactions, whereas
stresses that lack a DNA damage component, as exemplified
by hypoxia, primarily induce interaction with cosuppres-
sors. However, inhibition of either type of interaction can
result in diminished apoptotic activity. Germ line mutations
of the p53 tumor suppressor gene in patients with a high risk
for cancer inactivate the p53 protein (Colic & Pavelic,
2000). Lung-specific expression of the p53 and K-ras genes
in mice was reported by Witschi et al. (1999),Brockman et
al. (1992), and Wattenberg and Estensen (1996), when mice
were exposed to natural products, such as myo-inositol,
dexamethasone, curcumin, esculetin, resveratrol, lycopene,
and butylated hydroxyanisole. The question whether any of
the known natural products modulate expression of the p53
protein requires experimentation (Mann, 2002).
Carcinogens in the diet that trigger the initial stage
include moulds and aflatoxins (for example, in peanuts
and maize), nitrosamines (in smoked meats and other cured
products), rancid fats and cooking oils, alcohol, and addi-
tives and preservatives. A combination of foods may have a
cumulative effect, and when incorrect diet is added to a
polluted environment, smoking, UV radiation, free radicals,
lack of exercise, and stress, the stage is set for DNA damage
and cancer progression. In addition to the usual vitamin and
mineral supplements, amino acids such as cysteine and
natural antioxidants such as clove oil constituents are
particularly helpful in offsetting problems caused by a
variety of environmental toxins.
Many diseases, including cancer, have been shown to be
linked to a poorly functioning liver detoxification system. A
study at an Italian chemical plant showed that workers with
an inadequate liver detoxification enzyme later developed
bladder cancer. Herbs that promote a healthy liver function
include dandelion (taraxacum), milk thistle (silybum), and
artichoke (cynara). Beetroot is particularly beneficial and
may be eaten raw, cooked, or in juices. Raw vegetable
juices, which may include carrots, celery, and parsley,
together with beetroot are an excellent way of providing
concentrated antioxidants and plant enzymes (Stahl et al.,
2000). Wheat grass is also useful. A diet rich in cruciferous
vegetables and vitamins B (in whole grains and cereals) and
C (cabbage, broccoli, and brussel sprouts) promotes liver
detoxification. Other vitamin C foods are peppers, tomatoes,
oranges, and tangerines. Glutathione-rich foods, such as
avocados, asparagus, and walnuts, are also good for liver
detoxification. The current trend to identify natural products
as new cancer preventative agents is based on a conceptual
basis and understanding of their mechanisms of action in
carcinogenesis.
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–136
5.1. Antioxidants
Antioxidants are found in a wide variety fruits and
vegetables, plant extracts, beverages, herbs and spices, and
semisynthetics (Figs. 2 and 3 and Table 3). They have been
found to inhibit various types of cancers (Table 2). One of
the most important contributions to cancer is considered to
be oxidative damage to DNA. If a cell containing damaged
DNA divides before the DNA can be repaired, the result is
likely to be a permanent genetic alteration of the steps in
carcinogenesis. Body cells that divide rapidly are more
susceptible to carcinogenesis because there is less oppor-
tunity for DNA repair before cell division (Colic & Pavelic,
2000).
The mechanics for the protective effects of fruits and
vegetables and antioxidant nutrients appear to involve the
early rather than the later stages of carcinogenesis. There is
little doubt that oxidative stress can affect cancer cells in
several ways. There is compelling evidence that antioxi-
dants and antiinflammatory compounds (including anti-iron
and anti-copper compounds) could be used to modify the
redox environment of cancer cells and thus their behavior
(Schafer & Buettner, 2001). Additional explanation and
support for the concept that tumors contain high numbers
of mutated cells, which links this back to the ‘‘mutator
phenotype’’ theory, was proposed by Jackson and Loeb
(2001). As is consistent with a probable role of oxidative
stress in stimulating the mutator phenotype, there is evid-
ence that chronic inflammatory states are linked with
elevated cancer risk. It also suggests that antioxidants have
the potential to reduce the genetic instability of cancer cells
and thus may be useful in treatment. Reddy et al. (2001)
demonstrated a mechanism by which antioxidants can also
improve the efficacy of chemotherapy. Vitamin C at non-
toxic concentrations increased the cytotoxic effects of cis-
platin and etoposide against human cervical cancer cells in
vitro by stabilizing the p53 protein. However, in other
studies (Clement et al., 2001; Halliwell et al., 2000; Palozza
et al., 2001), it was shown that antioxidants, including
flavonoids and other phenolics, can induce oxidative stress
in cancer cells and that some or many of their effects seen in
vitro may be due to induction of such stress. b-Carotene at
Fig. 2. Chemical structures of flavonoids (Siess et al., 2000).
Fig. 3. Chemical structure of lycopene and related carotenoids (a- and b-carotene) (Kim et al., 2000a).
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–13 7
levels just above those seen in human plasma was shown to
induce apoptosis in human adenocarcinoma cells in vitro via
a free radical-mediated mechanism. Vitamin C was cyto-
toxic to several cell lines in vitro, again due to free radical
generation. These studies highlight the need to consider
redox effects when discussing the in vitro actions of anti-
oxidant compounds.
In vitro assessments of potential anticarcinogenesis effi-
cacy include measurements of an agent’s antioxidant activ-
ity, induction of phase II metabolizing enzymes, and effects
upon cellular proliferation and apoptotic control pathways.
In vivo efficacy is assessed primarily in rodent models of
carcinogenesis that are specific for a given organ target. The
role of genetically modified animal models in the in vivo
assessment of chemoprevention agents remains unclear.
Clinical assessment of the efficacy of a preventive agent
comprises a multistep process of identification of an optimal
preventive agent (phase 1), demonstration of efficacy in
humans through the modulation of reversal of tissue, bio-
chemical, and molecular surrogates for neoplastic trans-
formation and invasion (phase 2), and cancer risk
reduction in large cohort trials (phase 3). Opportunities
and future needs include the development of reliable,
predictive in vivo models of carcinogenesis, careful explora-
tion of the preventive pharmacology of therapeutic agents
being used for noncancer prevention indications, and
incorporation of genetic risk cohorts to define cancer
chemopreventive efficacy.
Vitamin C is known to interfere with the action of
nitrites, and further dietary intervention studies are under-
way to test the ability of ascorbic acid to reverse precancer-
ous lesions of the stomach. Vitamin E is a lipid-phase
scavenger of nitrite, oxygen-derived free radicals. However,
the evidence linking vitamin E and reduced cancer risks is
still inconclusive.
Kakagi et al. (2001) found that with adequate intake of
antioxidants during fish oil therapy chemoradiation-induced
immunosuppression in humans (1.8 g/day parenteral) can be
normalized. Moderate doses of dietary fish oil (4% of diet)
increased the efficacy of cisplatin against lung cancer cells
in mice. Fish oil and cisplatin were more effective than a
combination of fish oil, cisplatin, and vitamins C and E,
suggesting that oxidation of the fatty acids improved cell
kill (which is to be expected). However, even with the
antioxidants, the combination was more effective than
cisplatin alone (with soybean oil), demonstrating again that
fish oil works by multiple mechanisms and does not require
an oxidative action to affect tumor growth (Yam et al.,
2001). Similar evidence has also been found by Hardman et
al. (2001) in mice fed with fish oil (doses 3% of diet). There
was an increase in the efficacy of doxorubicin in mice
injected with breast cancer cells (Hardman et al., 2001).In
a human study (Aronson et al., 2001), daily oral adminis-
tration of 10 g of fish oil, along with vitamin E and a
healthy, low-fat diet, reduced cyclooxygenase expression in
prostatic tissue in 4 of 7 subjects. Since we know from in
vitro studies that eicosapentanoic acid reduces cyclooxyge-
nase expression, these are encouraging results, as they
suggest that such dietary interventions could reduce cyclo-
oxygenase expression and subsequent inflammation and
stimulation of tumour growth.
5.2. Fatty acids
Fatty acids also play an important role in tumor growth,
tumor inhibition, and cachexia. Hughes-Fulford et al. (2001)
found that cancer cells tend to be unresponsive to normal
cholesterol feedback, resulting in overexpression of the low-
density lipoprotein receptor. In turn, this allows excessive
uptake of low-density lipoprotein, the major carrier of
physiological arachidonic acid. Once in the cancer cell,
arachidonic acid acts as a substrate for the production of
various procancer prostaglandins and leukotrienes that
stimulate proliferation and progression. Uptake of w-3 fatty
acids does not have this stimulating effect. Sauer et al.
(2000) reported that eicosapentanoic acid inhibits fatty acid
uptake and its release in cancer cells and appears to act
through a putative w-3 fatty acid receptor. The inhibitory
effect of melatonin on fatty acid uptake is also mediated
though its cell surface receptor.
Currier and Miller (2001) reported that both melatonin
(0.57 mg/kg) and Echinacea extract given in the diet
improved the survival rate of mice injected with leukemia
cells. Melatonin given intraperitoneally to mice (4 mg/kg)
reduced the growth of a transplanted prostate cancer and a
transformed trophoblast cell line (Shiu et al., 2000; Xi et al.,
2001).
5.3. Amino acids and related compounds
Amino acids and other compounds normally found in
the blood act in concert as a sort of passive defense
system against the development of tumors. According to
Kulcsar (1995, 1997a,b), cancer cells are harmed by these
compounds because their uptake is unregulated, while
normal cells, which carefully regulate their uptake of
nutrients, are not adversely affected. One of the things
that is interesting in relation to natural compounds in
cancer therapy is that Kulcsar (2000) indicated that as
many as 13 compounds found in the blood act synergisti-
cally to inhibit cancer cell growth in vitro and in animals.
Liu et al. (2000) presented evidence that orally adminis-
tered glutamine inhibits tumor growth in animals. In this
case, administration of 300 mg/kg reduced the growth of
liver cancer cells injected into mice. The equivalent human
dose is 2.9 g/day. Further evidence for the role of
glutamine was provided in a randomized human study
by Daniele et al. (2001) who found that oral glutamine
reduced intestinal damage caused by chemotherapy. Sev-
enty colorectal cancer patients who had not yet received
chemotherapy were randomized to receive glutamine (18
g/day) or placebo. During treatment with chemotherapy
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–138
(5-FU and folinic acid), indexes of intestinal permeability
and absorption were improved in the group receiving
glutamine. In addition, the incidence of diarrhea was
reduced in the glutamine group.
Obrador et al. (2001) and Carretero et al. (2000) showed
that glutamine administration to tumor-bearing mice de-
creases mitochondrial glutathione concentrations in cancer
cells, leading to increased susceptibility to free radical
damage by tumour necrosis factor. Glutamine appeared to
act by inhibiting glutathione transport from the cytosol into
the mitochondria. Normal cells were not affected. Thus, the
result of glutathione administration is increased susceptibil-
ity of cancer cells to oxidative stress. Note that this
treatment does not increase oxidative stress per se, it only
makes cancer cells more susceptible. Furthermore, the
locale of the action appears to be the mitochondria, not
the nucleus. This suggests the possibility of using oxidative
stress as a treatment modality without increasing oxidative
damage to DNA; increasing reactive oxygen species within
the nucleus could, in theory, increase the mutation rate in
cells that are not destroyed.
Whey protein concentrate has also been found to produce
anticancer effects in humans with prostate cancer (Bounous,
2000).
5.4. Flavonoids
Flavonoids are the water-soluble pigments in vegetables,
fruits, grains, flowers, leaves, and bark. These pigments can
scavenge superoxide, hydroxy, and proxyradicals, breaking
lipid peroxide chain reactions. They have also been shown
to protect cells from X-ray damage, to block progression of
cell cycle, to inhibit mutations, to block prostaglandin
synthesis, and to prevent multistage carcinogenesis in
experimental animals (Abdulla & Gruber, 2000).
The chemical structures of the four common flavonoids
are illustrated in Fig. 3. According to Asea et al. (2001),
quercetin (found in onions) given intraperitoneally at 150
mg/kg/day reduced the growth of 2 different types of human
prostate cancer cells injected into mice. Isoflavones, phen-
olic acids, and genistein (found in soybeans) were found to
inhibit Jurkat T-leukemia cells and bladder cancer (Polkow-
ski & Mazurek, 2000; Siess et al., 2000; Spinozzi et al.,
1994; Theodorescu et al., 1998).
Nakagawa et al. (2000) demonstrated that genistein acts
synergistically with eicosapentanoic acid in inhibiting the
proliferation of human breast cancer cells in vitro. In this
study, genistein was reported to inhibit proliferation of
pancreatic cancer cells in vitro by a novel mechanism,
modulation of DNA synthesis by alteration of glucose
oxidation. This action needs to be further studied, but it
represents yet another means by which genistein could
inhibit tumor growth.
The absorption and metabolism of quercetin (and other
phenolics) is still poorly understood. For many years, it was
believed that quercetin, curcumin, and some other phenolics
were not absorbed at all, since no unchanged compound
could be measured in the plasma after oral administration. In
the last few years, it has become clear that these phenolics
are indeed absorbed but heavily metabolized prior to reach-
ing the plasma. Most of the metabolism is in the form of
glucuronidation or the formation of glucuronide conjugates.
However, the studies of Drewa et al. (2001) showed the
surprising result that quercetin given intraperitoneally to
mice at 2– 20 mg/kg/day increased the growth of injected
melanoma cells. It is not clear why this effect would be
seen, and since it suggests that quercetin could increase
tumor growth, caution has to be exercised.
Furthermore, the studies of Allred et al. (2001) reported
that oral administration of relatively low doses of genistein
(18 and 36 mg/kg) enhanced the growth of human breast
cancer cells injected into mice. The mice had their ovaries
removed to simulate estrogenic conditions of postmeno-
pausal women. This study does lend support for avoiding
genistein use in the treatment of estrogen-responsive tu-
mors.
In this 6-week study on rats with transplanted human
prostate cancer cells, oral administration of curcumin ( 1.5
g/kg) markedly inhibited tumor volume. Moreover, micro-
vessel density (a measure of angiogenesis) was decreased
and apoptosis was increased in the tumor tissue. Curcumin
was effective when administration was started either at the
time of tumor implantation or after establishment of solid
tumors. This dose is quite high; the human equivalent is
24 g/day (Dorai et al., 2001). Orally administered curcu-
min ( 240 and 1200 mg/kg) also reduced the development
of tumors after topical application of a carcinogen in mice
(Limtrakul et al., 2001). In this study, it was also shown that
curcumin also reduced the expression of ras and fos
oncogenes in the skin. The equivalent human doses are
2.3 and 11 g/day.
5.5. Resveratrol
Kimura and Okuda (2000) showed that oral administra-
tion to mice of resveratrol glycosides (as found naturally in
plants) for 32 consecutive days markedly reduced the
growth of implanted lung cancer cells and reduced meta-
stasis. Further studies (Kimura & Okuda, 2001) showed that
intraperitoneal administration of 2.5 and 10 mg/kg/day
inhibited tumor growth, metastasis, and tumor angiogenesis
of implanted lung cancer cells in mice. Brakenhielm et al.
(2001) demonstrated that oral administration of resveratrol
to mice in drinking water reduced the growth of injected
fibrosarcoma cells, apparently by inhibiting angiogenesis.
In vitro studies of Igura et al. (2001) added to the
literature on the mechanisms of cancer inhibition by resver-
atrol. Both resveratrol and quercetin inhibit aspects of
angiogenesis (proliferation, migration, and tube formation
of endothelial cells) at IC
50
between15and37mM.
Quercetin did not inhibit tube formation. Kozuki et al.
(2001) showed that resveratrol suppresses the invasion of
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–13 9
liver cancer cells at 25 mM, which was well below the
cytotoxic concentration. Importantly, sera from rats given
oral resveratrol also inhibited invasion in vitro. Nielsen et al.
(2000) reported that resveratrol at 50 mM improved gap
junction intercellular communication in liver cells exposed
to carcinogens. Lastly, Ahmad et al. (2001) and Wolter et al.
(2001) demonstrated that resveratrol ( 25 mM) inhibited
proliferation of colon and epidermoid cancer cells. In both
studies, inhibition appeared to be correlated to down-regu-
lation of cyclin-dependent kinases.
5.6. Alkaloids
Lately, it has been found that the naturally occurring bis-
benzylisoalkaloids (BBI) can reverse multidrug resistance
by increasing the intracellular drug accumulation through
inhibiting the activity of P-glycoprotein (Fu et al., 2001).
The BBI also show low cytotoxicity on tumor cells. This
could solve the problem conventional cancer chemotherapy
has with multidrug resistance, which has been linked to
overexpression of a membrane associated with P-glycopro-
tein that acts as an energy-dependent drug efflux pump.
5.7. Semisynthetic anticancer drugs
Most of the current cancer drugs are synthesized against
the backbone of one or another natural product (Table 5).
Anticancer drugs, such as paclitaxel and docetaxel, arise
from the taxol extracts of the English yew tree, Taxus spp.
(Fan, 1999), and are used to treat refractory ovarian, breast,
and other cancers. The inactive extracts of various plants are
chemically converted into drugs that affect cells at the
molecular level, thereby reversing or inhibiting tumorigen-
esis. Paclitaxel, for example, promotes tubulin assembly and
inhibits cell proliferation. Doxorubicin (from Streptomyces
peucetius) damages DNA by intercalation of the anthracy-
clin portion and causes metal ion chelation (Perry, 1992).
Camptothecin (from Camptotheca acuminata) inhibits the
action of topoisomerase I, resulting in cell death. Another
prominent molecule is podophyllotoxin, which has been
synthetically modified into etoposide and is used to treat
lung and testes cancer. Other important molecules include
vincristine, vinblastine, colchicine, ellipticine, flavopiridol
(a chromone alkaloid from Rohitukine), and a pyridoindole
alkaloid (from Ochrosia spp.) (Mukherjee et al., 2001).
6. Summary
The top two causes of cancer are related to dietary habits
and tobacco smoke, and as such, it is largely a preventable
disease. The incidence of cancer can thus be substantially
reduced by diet modification. Diets rich in vegetables, fruits,
and legumes contain large quantities of antioxidants that
protect against the deleterious action of free radicals that
may lead to cancer development. Consumption of reduced
amounts of red meats, saturated fat, salt, and sugar and the
avoidance of tobacco smoke and excess consumption of
alcohol are other diet modifications that have a positive
effect in the prevention of cancer.
It has been shown that whereas synthetic cancer drugs
cause nonspecific killing of cells, natural products offer
protective and therapeutic actions to all cells with low
cytotoxicity and are beneficial in producing nutrient reple-
tion to compromised people. A probing study into the
molecular program of apoptosis by cancer chemopreventive
agents indicates that the differential effects of studied
compounds on distinct molecular pathways of apoptosis
warrants further investigation in the effort to utilise the
molecular elements of apoptosis in proper cancer chemo-
Table 5
Semisynthetic chemoprotective products commonly used as cancer drugs
Source Inactive component/active
(semisynthetic) component
Mechanism of action Cancer inhibited (reference)
Taxus baccata 10-Deacetyl baccatin 111:
Docetaxel
Promotes tubulin assembly and inhibition of
microtubule depolymerization; also acts as a
mitotic spindle poison and induces mitotic block
in proliferative cells
Breast, ovarian, nonsmall cell lung, head and
neck, colorectal, melanoma (Aapro, 1998;
Sjostrom et al., 1999)
Taxus brevifolia Diterpenoid, paclitaxel/taxol Promotes assembly of microtubules, stabilizes
them against depolymerization, and inhibits cell
replication; causes apoptosis
Advanced breast, ovarian, adenocarcinoma,
and other solid tumors (Fan, 1999; Huang &
Fan, 2002; Johnson & Fan, 2002; Johnson
et al., 1997)
Streptomyces
peucetius
Daunorubicin, doxorubicin Damages DNA by intercalation of anthracyclin
portion, metal ion chelation, generation of free
radicals, inhibits DNA topoisomerase 11
Leukemia, breast, Hodgkin’s, non-Hodgkin’s,
lung, small cell, ovarian cancer and sarcomas
(Perry, 1992; Zeng et al., 2000)
Rohitukine
(Indian plant)
Flavopiridol CDK modulator Various cancers (Malumbres & Barbacid,
2001; Mukherjee et al., 2001)
Camptotheca
acuminata
10-Hydroxy camptothecin,
irinotecan (CPT-11),
SN-38
Inhibits action of topoisomerase I, prevents
religation of DNA strand, results in cell death
Liver, colorectal, head and neck cancer,
leukemia (Chabot, 1997; Friedman et al.,
1999; Jiang et al., 2000; Zhang et al., 1998)
L. Reddy et al. / Pharmacology & Therapeutics 99 (2003) 1–1310
prevention and to find biochemical targets for apoptosis-
related surrogate end point biomarker assays of chemo-
prevention.
Acknowledgments
We are particularly grateful to the Medical Research
Council and the National Research Foundation, South
Africa for research grant support.
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