Cancer is a Preventable Disease that Requires Major Lifestyle Changes
Ajaikumar B. Kunnumakara,
Kuzhuvelil B. Harikumar,
Sheeja T. Tharakan,
Oiki S. Lai,
and Bharat B. Aggarwal
Received May 14, 2008; accepted June 9, 2008; published online July 15, 2008
Abstract. This year, more than 1 million Americans and more than 10 million people worldwide are
expected to be diagnosed with cancer, a disease commonly believed to be preventable. Only 5–10% of all
cancer cases can be attributed to genetic defects, whereas the remaining 90–95% have their roots in the
environment and lifestyle. The lifestyle factors include cigarette smoking, diet (fried foods, red meat),
alcohol, sun exposure, environmental pollutants, infections, stress, obesity, and physical inactivity. The
evidence indicates that of all cancer-related deaths, almost 25–30% are due to tobacco, as many as 30–
35% are linked to diet, about 15–20% are due to infections, and the remaining percentage are due to
other factors like radiation, stress, physical activity, environmental pollutants etc. Therefore, cancer
prevention requires smoking cessation, increased ingestion of fruits and vegetables, moderate use of
alcohol, caloric restriction, exercise, avoidance of direct exposure to sunlight, minimal meat consumption,
use of whole grains, use of vaccinations, and regular check-ups. In this review, we present evidence that
inﬂammation is the link between the agents/factors that cause cancer and the agents that prevent it. In
addition, we provide evidence that cancer is a preventable disease that requires major lifestyle changes.
KEY WORDS: cancer; environmental risk factors; genetic risk factors; prevention.
After sequencing his own genome, pioneer genomic
researcher Craig Venter remarked at a leadership for the
twenty-ﬁrst century conference, “Human biology is actually far
more complicated than we imagine. Everybody talks about the
genes that they received from their mother and father, for this
trait or the other. But in reality, those genes have very little
impact on life outcomes. Our biology is way too complicated for
that and deals with hundreds of thousands of independent
factors. Genes are absolutely not our fate. They can give us
useful information about the increased risk of a disease, but in
most cases they will not determine the actual cause of the
disease, or the actual incidence of somebody getting it. Most
biology will come from the complex interaction of all the
proteins and cells working with environmental factors, not
driven directly by the genetic code” (http://indiatoday.digitalto
This statement is very important because looking to the
human genome for solutions to most chronic illnesses,
including the diagnosis, prevention, and treatment of cancer,
is overemphasized in today ’s world. Observational studies,
however, have indicated that as we migrate from one country
to another, our chances of being diagnosed with most chronic
illnesses are determined not by the country we come from but
by the country we migrate to (1–4). In addition, studies with
identical twins have suggested that genes are not the source
of most chronic illnesses. For instance, the concordance
between identical twins for breast cancer was found to be
only 20% (5). Instead of our genes, our lifestyle and
environment account for 90 –95% of our most chronic
Cancer continues to be a worldwide killer, despite the
enormous amount of research and rapid developments seen
during the past decade. According to recent statistics, cancer
accounts for about 23% of the total deaths in the USA and is
the second most common cause of death after heart disease
(6). Death rates for heart disease, however, have been steeply
decreasing in both older and younger populations in the USA
from 1975 through 2002. In contrast, no appreciable differ-
ences in death rates for cancer have been observed in the
United States (6).
By 2020, the world population is expected to have
increased to 7.5 billion; of this number, approximately 15 million
new cancer cases will be diagnosed, and 12 million cancer
patients will die (7). These trends of cancer incidence and death
rates again remind us of Dr. John Bailer’sMay1985judgment
of the US national cancer program as a “qualiﬁed failure,” a
judgment made 14 years after President Nixon’sofﬁcial
declaration of the “War on Cancer.” Even after an additional
quarter century of extensive research, researchers are still
trying to determine whether cancer is preventable and are
asking “If it is preventable, why are we losing the war on
cancer?” In this review, we attempt to answer this question by
2008 Springer Science + Business Media, LLC
Pharmaceutical Research, Vol. 25, No. 9, September 2008 (
Cytokine Research Laboratory, Department of Experimental Ther-
apeutics, The University of Texas M. D. Anderson Cancer Center,
1515 Holcombe Boulevard, Houston, Texas 77030, USA.
To whom correspondence should be addressed. (e-mail: aggar
analyzing the potential risk factors of cancer and explore our
options for modulating these risk factors.
Cancer is caused by both internal factors (such as
inherited mutations, hormones, and immune conditions) and
environmental/acquired factors (such as tobacco, diet, radia-
tion, and infectious organisms; Fig. 1). The link between diet
and cancer is revealed by the large variation in rates of
speciﬁc cancers in various countries and by the observed
changes in the incidence of cancer in migrating. For example,
Asians have been shown to have a 25 times lower incidence
of prostate cancer and a ten times lower incidence of breast
cancer than do residents of Western countries, and the rates
for these cancers increase substantially after Asians migrate
to the West (http://www.dietandcancerreportorg/?p=ER).
The importance of lifestyle factors in the development of
cancer was also shown in studies of monozygotic twins (8).
Only 5–10% of all cancers are due to an inherited gene
defect. Various cancers that have been linked to genetic
defects are shown in Fig. 2. Although all cancers are a result
of multiple mutations ( 9, 10), these mutations are due to
interaction with the environment (11, 12).
These observations indicate that most cancers are not of
hereditary origin and that lifestyle factors, such as dietary
habits, smoking, alcohol consumption, and infections, have a
profound inﬂuence on their development (13). Although the
hereditary factors cannot be modiﬁed, the lifestyle and
environmental factors are potentially modiﬁable. The lesser
hereditary inﬂuence of cancer and the modiﬁable nature of
the environmental factors point to the preventability of
cancer. The important lifestyle factors that affect the inci-
dence and mortality of cancer include tobacco, alcohol, diet,
obesity, in fectious agents, environmental pollutants, and
RISK FACTORS OF CANCER
Smoking was identiﬁed in 1964 as the primary cause of
lung cancer in the US Surgeon General’s Advisory Commis-
sion Report (http://proﬁles.nlm.nih.gov/NN/Views/Alpha
Chron/date/10006/05/01/2008), and ever since, efforts have
been ongoing to reduce tobacco use. Tobacco use increases
the risk of developing at least 14 types of cancer (Fig. 3). In
addition, it accounts for about 25–30% of all deaths from
cancer and 87% of deaths from lung cancer. Compared with
Fig. 1. The role of genes and environment in the development of cancer. A The percentage contribution of
genetic and environmental factors to cancer. The contribution of genetic factors and environmental factors
towards cancer risk is 5–10% and 90–95% respectively. B Family risk ratios for selected cancers. The
numbers represent familial risk ratios, deﬁned as the risk to a given type of relative of an affected individual
divided by the population prevalence. The data shown here is taken from a study conducted in Utah to
determine the frequency of cancer in the ﬁrst-degree relatives (parents + siblings + offspring). The familial
risk ratios were assessed as the ratio of the observed number of cancer cases among the ﬁrst degree relatives
divided by the expected number derived from the control relatives, based on the years of birth (cohort) of
the case relatives. In essence, this provides an age-adjusted risk ratio to ﬁrst-degree relatives of cases
compared with the general population. C Percentage contribution of each environmental factor. The
percentages represented here indicate the attributable-fraction of cancer deaths due to the speciﬁed
environmental risk factor.
2098 Anand et al.
nonsmokers, male smokers are 23 times and female smokers
17 times more likely to develop lung cancer (http://www.
Figures_2008.asp accessed on 05/01/2008). The carcinogenic
effects of active smoking are well documented; the U. S.
Environmental Protection Agency, for example, in 1993
classiﬁed environmental tobacco smoke (from passive smok-
ing) as a known (Group A) human lung carcinogen (http://
accessed on 05/01/2008). Tobacco contains at least 50
carcinogens. For example, one tobacco metabolite, benzopyr-
enediol epoxide, has a direct etiologic association with lung
cancer (14). Among all developed countries considered in
total, the prevalence of smoking has been slowly declining;
however, in the developing countries where 85% of the
world’s population resides, the prevalence of smoking is
(MLH1, MSH2, MSH6, PMS2
APC, DPC4, Bmpr1, PTEN, MYH)
Breast & ovarian cancer
(BRCA1 and BRCA2)
(HPC1, TLR1, TLR4, TLR6, TLR9)
Chronic myeloid leukemia
Multiple endocrine neoplasia
Fig. 2. Genes associated with risk of different cancers.
Fig. 3. Cancers that have been linked to alcohol and smoking. Percentages represent the cancer mortality
attributable to alcohol and smoking in men and women as reported by Irigaray et al. (see 13).
2099Cancer Prevention Requires Major Lifestyle Changes
increasing. According to studies of recent trends in tobacco
usage, developing countries will consume 71% of the world’s
tobacco by 2010, with 80% increased usage projected for East
Asia (ht tp://www.fao.org/DOCREP/006 /Y4956E/Y4956E00.
HTM accessed on 01/11/08). The use of accelerated tobacco-
control programs, with an emphasis in areas where usage is
increasing, will be the only way to redu ce the rates of
tobacco-related cancer mortality.
How smoking contributes to cancer is not fully understood.
We do know that smoking can alter a large number of cell-
signaling pathways. Results from studies in our group have
established a link between cigarette smoke and inﬂammation.
Speciﬁcally, we showed that tobacco smoke can induce activa-
tion of NF-κB, an inﬂammatory marker (15,16). Thus, anti-
inﬂammatory agents that can suppress NF-κB activation may
have potential applications against cigarette smoke.
We also showed that curcumin, derived from the dietary
spice turmeric, can block the NF-κB induced by cigarette
smoke (15). In addition to curcumin, we discovered that
several natural phytochemicals also inhibit the NF-κB in-
duced by various carcinogens (17). Thus, the carcinogenic
effects of tobacco appear to be reduced by these dietary
agents. A more detailed discussion of dietary agents that can
block inﬂammation and thereby provide chemopreventive
effects is presented in the following section.
The ﬁrst report of the association between alcohol and
an increased risk of esophageal cancer was published in 1910
(18). Since then, a number of studies have revealed that
chronic alcohol consumption is a risk factor for cancers of the
upper aerodigestive tract, including cancers of the oral cavity,
pharynx, hypopharynx, larynx, and esophagus (18–21), as
well as for cancers of the liver, pancreas, mouth, and breast
(Fig. 3). Williams and Horn (22), for example, reported an
increased risk of breast cancer due to alcohol. In addition, a
collaborative group who studied hormonal factors in breast
cancer published their ﬁndings from a reanalysis of more than
80% of individual epidemiological studies that had been
conducted worldwide on the association between alcohol and
breast cancer risk in women. Their analysis showed a 7.1%
increase in relative risk of breast cancer for each additional
10 g/day intake of alcohol (23). In another study, Longnecker
et al., (24) showed that 4% of all newly diagnosed cases of
breast cancer in the USA are due to alcohol use. In addition
to it being a risk factor for breast cancer, heavy intake of
alcohol (more than 50–70 g/day) is a well-established risk
factor for liver (25) and colorectal (26,27) cancers.
There is also evidence of a synergistic effect between
heavy alcohol ingestion and hepatitis C virus (HCV) or
hepatitis B virus (HBV), which presumably increases the risk
of hepatocellular carcinoma (HCC) by more actively promot-
ing cirrhosis. For example, Donato et al.(28) reported that
among alcohol drinkers, HCC risk increased linearly with a
daily intake of more than 60 g. However, with the concom-
itant presence of HCV infection, the risk of HCC was two
times greater than that observed with alcohol use alone (i.e., a
positive synergistic effect). The relationship between alcohol
and inﬂammation has also been well established, especially in
terms of alcohol-induced inﬂammation of the liver.
How alcohol contributes to carcinogenesis is not fully
understood but ethanol may play a role. Study ﬁndings
suggest that ethanol is not a carcinogen but is a cocarcinogen
(29). Speciﬁcally, when ethanol is metabolized, acetaldehyde
and free radicals are generated; free radicals are believed to
be predominantly responsible for alcohol-associated carcino-
genesis through their binding to DNA and proteins, which
destroys folate and results in secondary hyperproliferation.
Other mechanisms by which alcohol stimulates carcinogenesis
include the induction of cytochrome P-4502E1, which is
associated with enhanced production of free radicals and
enhanced activation of various procarcinogens present in
alcoholic beverages; a change in metabolism and in the
distribution of carcinogens, in association with tobacco smoke
and diet; alterations in cell-cycle behavior such as cell-cycle
duration leading to hyperproliferation; nutritional deﬁcien-
cies, for example, of methyl, vitamin E, folate, pyridoxal
phosphate, zinc, and selenium; and alterations of the immune
system. Tissue injury, such as that occurring with cirrhosis of
the liver, is a major prerequisite to HCC. In addition, alcohol
can activate the NF-κB proinﬂammatory pathway (30), which
can also contribute to tumorigenesis (31). Furthermore, it has
been shown that benzopyrene, a cigarette smoke carcinogen,
can penetrate the esophagus when combined with ethanol
(32). Thus anti-inﬂammatory agents may be effective for the
treatment of alcohol-induced toxicity.
In the upper aerodigestive tract, 25–68% of cancers are
attributable to alcohol, and up to 80% of these tumors can be
prevented by abstaining from alcohol and smoking (33).
Globally, the attributable fraction of cancer deaths due to
alcohol drinking is reported to be 3.5% (34). The number of
deaths from cancers known to be related to alcohol con-
sumption in the USA could be as low as 6% (as in Utah) or as
high as 28% (as in Puerto Rico). These numbers vary from
country to country, and in France have approached 20% in
In 1981, Doll and Peto (21) estimated that approximately
30–35% of cancer deaths in the USA were linked to diet
(Fig. 4). The extent to which diet contributes to cancer deaths
varies a great deal, according to the type of cancer (35). For
example, diet is linked to cancer deaths in as many as 70% of
colorectal cancer cases. How diet contributes to cancer is not
fully understood. Most carcinogens that are ingested, such as
nitrates, nitrosamines, pesticides, and dioxins, come from
food or food additives or from cooking.
Heavy consumption of red meat is a risk factor for
several cancers, especially for those of the gastrointestinal
tract, but also for colorectal (36–38), prostate (39), bladder
(40), breast (41), gastric (42), pancreatic, and oral (
cancers. Although a study by Dosil-Diaz et al., (44) showed
that meat consumption reduced the risk of lung cancer, such
consumption is commonly regarded as a risk for cancer for
the following reasons. The heterocyclic amines produced
during the cooking of meat are carcinogens. Charcoal cooking
and/or smoke curing of m eat produces harmful carbon
compounds such as pyrolysates and amino acids, which have
a strong cancerous effect. For instance, PhIP (2-amino-1-
methyl-6-phenyl-imidazo[4,5-b]pyridine) is the most abun-
2100 Anand et al.
dant mutagen by mass in cooked beef and is responsible for
~20% of the total mutagenicity found in fried beef. Daily
intake of PhIP among Americans is estimated to be 280–
460 ng/day per person (45).
Nitrites and nitrates are used in meat because they bind
to myoglobin, inhibiting botulinum exotoxin production;
however, they are powerful carcinogens (46 ). Long-term
exposure to food additives such as nitrite preservatives and
azo dyes has been associated with the induction of carcino-
genesis (47). Furthermore, bisphenol from p lastic food
containers can migrate into food and may increase the risk
of breast (48) and prostate (49) cancers. Ingestion of arsenic
may increase the risk of bladder, kidney, liver, and lung
cancers (50). Saturated fatty acids, trans fatty acids, and
reﬁned sugars and ﬂour present in most foods have also been
associated with various cancers. Several food carcinogens
have been shown to activate inﬂammatory pathways.
According to an American Cancer Society study (51),
obesity has been associated with increased mortality from
cancers of the colon, breast (in postmenopausal women),
endometrium, kidneys (renal cell), esophagus (adenocarcino-
ma), gastric cardia, pancreas, prostate, gallbladder, and liver
(Fig. 5). Findings from this study suggest that of all deaths
from cancer in the United States, 14% in men and 20% in
women are attributable to excess weight or obesity. Increased
modernization and a Westernized diet and lifestyle have been
associated with an increased prevalence of overweight people
in many developing countries (52).
Studies have shown that the common denominators
between obesity and cancer include neurochemicals; hor-
mones such as insulinlike growth factor 1 (IGF-1), insulin,
leptin; sex steroids; adiposity; insulin resistance; and inﬂam-
Involvement of signaling pathways such as the IGF/
insulin/Akt signaling pathway, the leptin/JAK/STAT pathway,
and other inﬂammatory cascades have also been linked with
both obesity and cancer ( 53). For instance, hyperglycemia,
has been shown to activate NF-κB(54), which could link
obesity with can cer. Also known to activate NF-κB are
several cytokines produced by adipocytes, such as leptin,
tumor necrosis factor (TNF), and interleukin-1 (IL-1) (55).
Energy balance and carcinogenesis has been closely linked
(53). However, whether inhibitors of these signaling cascades
can reduce obesity-related cancer risk remains unanswered.
Because of the involvement of multiple signaling pathways, a
potential multitargeting agent will likely be needed to reduce
obesity-related cancer risk.
Worldwide, an estimated 17.8% of neoplasms are associat-
ed with infections; this percentage ranges from less than 10% in
high-income countries to 25% in African countries (56, 57).
Viruses account for most infection-caused cancers (Fig. 6).
Human papillomavirus, Epstein Barr virus, Kaposi’s sarcoma-
associated herpes virus, human T-lymphotropic virus 1, HIV,
HBV, and HCV are associated with risks for cervical cancer,
anogenital cancer, skin cancer, nasopharyngeal cancer, Bur-
kitt’s lymphoma, Hodgkin
’s lymphoma, Kaposi’s sarcoma,
adult T-cell leukemia, B-cell lymphoma, and liver cancer.
In Western developed countries, human papillomavirus
and HBVare the most frequently encountered oncogenic DNA
viruses. Human papillomavirus is directly mutagenic by induc-
ing the viral genes E6 and E7 (58), whereas HBV is believed to
be indirectly mutagenic by generating reactive oxygen species
through chronic inﬂammation (59–61). Human T-lymphotropic
virus is directly mutagenic, whereas HCV (like HBV) is
believed to produce oxidative stress in infected cells and thus
to act ind irectly through chronic inﬂammation (62, 63).
However, other microorganisms, including selected parasites
such as Opisthorchis viverrini or Schistosoma haematobium and
bacteria such as Helicobacter pylori, may also be involved,
acting as cofactors and/or carcinogens (64).
Gall bladder cancer
Fig. 4. Cancer deaths (%) linked to diet as reported by Willett (see 35).
2101Cancer Prevention Requires Major Lifestyle Changes
The mechanisms by which infectious agents promote
cancer are becoming increasingly evident. Infection-related
inﬂammation is the major risk factor for cancer, and almost
all viruses linked to cancer have been shown to activate the
inﬂammatory marker, NF-κB(65). Similarly, components of
Helicobacter pylori have been shown to activate NF-κB(66).
Thus, agents that can block chronic inﬂammation should be
effective in treating these conditions.
Gall bladder cancer
Fig. 5. Various cancers that have been linked to obesity. In the USA overweight and obesity could account
for 14% of all deaths from cancer in men and 20% of those in women (see 51).
(HPV-6, HPV-16, HPV-18)
Adult T cell leukemia,
Merkel cell carcinoma
(Merkel cell polyvirus)
Fig. 6. Various cancers that have been linked to infection. The estimated total of infection attributable cancer in the
year 2002 is 17.8% of the global cancer burden. The infectious agents associated with each type of cancer is shown
in the bracket. HPV Human papilloma virus, HTLV human T-cell leukemia virus, HIV human immunodeﬁciency
virus, EBV Epstein–Barr virus (see 57).
2102 Anand et al.
Envir onmental pollution has been linked to various
cancers (Fig. 7). It includes outdoor air pollution by carbon
particles associated with polycyclic aromatic hydrocarbons
(PAHs) ; ind oor air pollution by en vironmental tobacco
smoke, formaldehyde, and volatile organic compounds such
as benzene and 1,3-butadiene (which may particularly affect
children); food pollution by food additives and by carcino-
genic contaminants such as nitrates, pesticides, dioxins, and
other organochlorines; carcinogenic metals and metalloids;
pharmaceutical medicines; and cosmetics (64).
Numerous outdoor air pollutants such as PAHs increase
the risk of cancers, especially lung cancer. PAHs can adhere
to ﬁne carbon particles in the atmosphere and thus penetrate
our bodies primarily through breathing. Long-term exposure
to PAH-containing air in polluted cities was found to increase
the risk of lung cancer deaths. Aside from PAHs and other
ﬁne carbon particles, another environmental pollutant, nitric
oxide, was found to increase the risk of lung cancer in a
European population of nonsmokers. Other studies have
shown that nitric oxide can induce lung cancer and promote
metastasis. The increased risk of childhood leukemia associ-
ated with exposure to motor vehicle e xhaust was also
Indoor air pollutants such as volatile organic compounds
and pesticides increase the risk of childhood leukemia and
lymphoma, and children as well as adults exposed to
pesticides have increased risk of brain tumors, Wilm’s tumors,
Ewing’s sarcoma, and germ cell tumors. In utero exposure to
environmental organic pollutants was found to increase the
risk for testicular cancer. In addition, dioxan, an environmen-
tal pollutant from incinerators, was found to increase the risk
of sarcoma and lymphoma.
Long-term exposure to chlorinated drinking water has
been associated with increased risk of cancer. Nitrates, in
drinking water, can transform to mutagenic N-nitroso com-
pounds, which increase the risk of lymphoma, leukemia,
colorectal cancer, and bladder cancer (64).
Up to 10% of total cancer cases may be induced by
radiation (64), both ionizing and nonionizing, typically from
radioactive substances and ultraviolet (UV), pulsed electro-
magnetic ﬁelds. Cancers induced by radiation include some
types of leukemia, lymphoma, thyroid cancers, skin cancers,
sarcomas, lung and breast carcinomas. One of the best
examples of increased r isk of cancer after exposure to
radiation is the increased incidence of total malignancies
observed in Sweden after exposure to radioactive fallout from
the Chernobyl nuclear power plant. Radon and radon decay
products in the home and/or at workplaces (such as mines)
are t he most common sources of exposure to ionizing
radiation. The presence of radioactive nuclei from radon,
radium, and uranium was found to increase the risk of gastric
cancer in rats. Another source of radiation exposure is x-rays
used in medical settings for diagnostic or therapeutic pur-
poses. In fact, the risk of breast cancer from x-rays is highest
among girls exposed to chest irradiation at puberty, a time of
intense breast development. Other factors associated with
radiation-induced cancers in humans are patient age and
physiological state, synergistic interactions between radiation
and carcinogens, and genetic susceptibility toward radiation.
Childhood leukemia & lymphoma,
brain tumors, Wilms’ tumors,
Ewing’s sarcoma, germ cell tumors
(Env. Organic pollutants)
Sarcoma & Lymphoma
Bladder cancer, colorectal cancer,
(Chlorinated drinking water)
Leukemia, lymphoma &
[carbon, radium and uranium]
Lung cancer Metastasis
Fig. 7. Various cancers that have been linked to environmental carcinogens. The carcinogens linked to each cancer
is shown inside bracket. (see 64).
2103Cancer Prevention Requires Major Lifestyle Changes
Nonionizing radiation derived primarily from sunlight
includes UV rays, which are carcinogenic to humans. Exposure
to UV radiation is a major risk for various types of skin cancers
including basal cell carcinoma, squamous cell carcinoma, and
melanoma. Along with UVexposure from sunlight, UVexposure
from sunbeds for cosmetic tanning may account for the growing
incidence of melanoma. Depletion of the ozone layer in the
stratosphere can augment the dose-intensity of UVB and UVC,
which can further increase the incidence of skin cancer.
Low-frequency electromagnetic ﬁelds can cause clasto-
genic DNA damage. The sources of electromagnetic ﬁeld
exposure are high-voltage power lines, transformers, electric
train engines, and more generally, all types of electrical
equipments. An increased risk of cancers such as childhood
leukemia, brain tumors and breast cancer has been attributed
to electromagnetic ﬁeld exposure. For instance, children
living within 200 m of high-voltage power lines have a relative
risk of leukemia of 69%, whereas those living between 200
and 600 m from these power lines have a relative risk of 23%.
In addition, a recent meta-analysis of all available epidemi-
ologic data showed that daily prolonged use of mobile phones
for 10 years or more showed a consistent pattern of an
increased risk of brain tumors (64).
PREVENTION OF CANCER
The fact that only 5–10% of all cancer cases are due to
genetic defects and that the remaining 90–95% are due to
environment and lifestyle provides major opportunities for
preventing cancer. Because tobacco, diet, infection, obesity,
and other factors contribute approximately 25–30%, 30–35%,
15–20%, 10–20%, and 10–15%, respectively, to the incidence
of all cancer deaths in the USA, it is clear how we can prevent
cancer. Almost 90% of patients diagnosed with lung cancer
are cigarette smokers; and cigarette smoking combined with
alcohol intake can synergistically contribute to tumorigenesis.
Similarly, smokeless tobacco is responsible for 400,000 cases
(4% of all cancers) of oral cancer worldwide. Thus avoidance
of tobacco products and minimization of alcohol consumption
would likely have a major effect on cancer incidence.
Infection by various bacteria and viruses (Fig. 6)is
another very prominent cause of various cancers. Vaccines for
cervical cancer and HCC should help prevent some of these
cancers, and a cleaner environment and modiﬁed lifestyle
behavior would be even more helpful in preventing infection-
The ﬁrst FDA approved chemopreventive agent was
tamoxifen, for reducing the risk of breast cancer. This agent
was found to reduce the breast cancer incidence by 50% in
women at high risk. With tamoxifen, there is an increased risk of
serious side effects such as uterine cancer, blood clots, ocular
disturbances, hypercalcemia, and stroke (http://www.fda.gov/
cder/foi/appletter/1998/17970s40.pdf). Recently it has been
shown that a osteoporosis drug raloxifene is as effective as
tamoxifen in preventing estrogen-receptor-positive, invasive
breast cancer but had fewer side effects than tamoxifen.
Though it is better than tamoxifen with respect to side effects,
it can cause blood clots and stroke. Other potential side effects
of raloxifene include hot ﬂashes, leg cramps, swelling of the
legs and feet, ﬂu-like symptoms, joint pain, and sweating
The second chemopreventive agent to reach to clinic was
ﬁnasteride, for prostate cancer, which was found to reduce
incidence by 25% in men at high risk. The recognized side
effects of this agent include erectile dysfunction, lowered
sexual desire, impotence and gynecomas tia (http://www.
cancer.org/docroot/cri/content/cri_2_4_2x_ can_prosta te_c an
cer_be_prevented_36.asp). Celecoxib, a COX-2 inhibitor is
another approved agent for prevention of familial adenoma-
tous polyposis (FAP). However, the chemopreventive beneﬁt
of celecoxib is at the cost of its serious cardiovascular harm
Memo.pdf). The serious side effects of the FDA approved
chemopreventive drugs is an issue of particular concern when
considering long-term administration of a drug to healthy
people who may or may not develop cancer. This clearly
indicates the need for agents, which are safe and efﬁcacious in
preventing cancer. Diet derived natural products will be
potential candidates for this purpose.
Diet, obesity, and metabolic syndrome are very much
linked to various cancers and may account for as much as 30–
35% of cancer deaths, indicating that a reasonably good
fraction of cancer deaths can be prevented by modifying the
diet. Extensive research has revealed that a diet consisting of
fruits, vegetables, spices, and grains has the potential to
prevent cancer (Fig. 8). The speciﬁc substances in these
dietary foods that are responsible for preventing cancer and
the mechanisms by which they achieve this have also been
examined extensively. Various phytochemicals have been
identiﬁed in fruits, vegetables, spices, and grains that exhibit
chemopreventive potential (Fig. 9), and numerous studies
have shown that a proper diet can help protect against cancer
(46, 67–69). Below is a description of selected dietary agents
and diet-derived phytochemicals that have been studied
extensively to determine their role in cancer prevention.
Fruits and Vegetables
The protective role of fruits and vegetables against cancers
that occur in various anatomical sites is now well supported
(46,69). In 1966, Wattenberg (70) proposed for the ﬁrst time
that the regular consumption of certain constituents in fruits
and vegetables might provide protection from cancer. Doll and
Peto (21) showed that 75–80% of cancer cases diagnosed in the
USA in 1981 might have been prevented by lifestyle changes.
According to a 1997 estimate, approximately 30–40% of cancer
cases worldwide were preventable by feasible dietary means
(http://www.dietandcancerreportorg/?p=ER). Several studies
have addressed the cancer chemopreventive effects of the
active components derived from fruits and vegetables.
More than 25,000 different phytochemicals have been
identiﬁed that may have potential against various cancers.
These phytochemicals have advantages because they are safe
and us ually target multiple cell-signaling pathways (71).
Major chemopreventive compounds identiﬁed from fruits
and vegetables includes carotenoids, vitamins, resveratrol,
quercetin, silymarin, sulphoraphane and indole-3-carbinol.
Various natural carotenoids present in fruits and vegeta-
bles were reported to have anti-inﬂammatory and anticarci-
2104 Anand et al.
nogenic activity. Lycopene is one of the main carotenoids in
the regional Mediterranean diet and can account for 50% of
the carotenoids in human serum. Lycopene is present in
fruits, including watermelon, apricots, pink guava, grapefruit,
rosehip, and tomatoes. A wide variety of processed tomato-
based produc ts acc ount for more than 85% of dietary
lycopene. The anticancer activity of lycopene has been
demonstrated in both in vitro and in vivo tumor models as
well as in humans. The proposed mechanisms for the
anticancer effect of lycopene involve ROS scavenging, up-
regulation of detoxiﬁcation systems, interference with cell
prolifer ation, ind uction of gap-junctional communication,
inhibition of cell-cycle progression, and modulation of signal
transduction pathways. Other carotenoids reported to have
anticancer activity include beta-carotene, alpha-carotene,
lutein, zeaxanthin, beta-cryptoxanthin, fucoxanthin, astaxan-
thin, capsanthin, crocetin, and phytoene (72).
The stilbene resveratrol has been found in fruits such as
grapes, peanuts, and berries. Resveratrol exhibits anticancer
properties against a wide va riety of tumors, including
lymphoid and myeloid cancers, multiple myeloma, and
cancers of the breast, prostate, stomach, colon, and pancreas.
The growth-inhibitory effects of resveratrol are mediated
through cell-cycle arrest; induction of apoptosis via Fas/
CD95, p53, ceramide activation, tubulin polymerization,
mitochondrial and adenylyl cyclase pathways; up-regulation
of p21 p53 and Bax; down-regulation of survivin, cyclin D1,
Spices & condiments
Fig. 8. Fruits, vegetables, spices, condiments and cereals with potential to prevent cancer. Fruits include 1 apple, 2 apricot, 3 banana, 4 blackberry, 5
cherry, 6 citrus fruits, 7 dessert date, 8 durian, 9 grapes, 10 guava, 11 Indian gooseberry, 12 mango, 13 malay apple, 14 mangosteen, 15 pineapple,
16 pomegranate. Vegetables include 1 artichok, 2 avocado, 3 brussels sprout, 4 broccoli, 5 cabbage, 6 cauliﬂower, 7 carrot, 8 daikon 9 kohlrabi, 10
onion, 11 tomato, 12 turnip, 13 ulluco, 14 water cress, 15 okra, 16 potato, 17 ﬁddle head, 18 radicchio, 19 komatsuna, 20 salt bush, 21 winter squash,
22 zucchini, 23 lettuce, 24 spinach. Spices and condiments include 1 turmeric, 2 cardamom, 3 coriander, 4 black pepper, 5 clove, 6 fennel, 7
rosemary, 8 sesame seed,
9 mustard, 10 licorice, 11 garlic, 12 ginger, 13 parsley, 14 cinnamon, 15 curry leaves, 16 kalonji, 17 fenugreek, 18 camphor,
19 pecan, 20 star anise, 21 ﬂax seed, 22 black mustard, 23 pistachio, 24 walnut, 25 peanut, 26 cashew nut. Cereals include 1 rice, 2 wheat, 3 oats, 4
rye, 5 barley, 6 maize, 7 jowar, 8 pearl millet, 9 proso millet, 10 foxtail millet, 11 little millet, 12 barnyard millet, 13 kidney bean, 14 soybean, 15
mung bean, 16 black bean, 17 pigeon pea, 18 green pea, 19 scarlet runner bean, 20 black beluga, 21 brown spanish pardina, 22 green, 23 green
(eston), 24 ivory white, 25 multicolored blend, 26 petite crimson, 27 petite golden, 28 red chief.
2105Cancer Prevention Requires Major Lifestyle Changes
cyclin E, Bcl-2, Bcl-xL, and cellular inhibitor of apoptosis
proteins; activation of caspases; suppression of nitric oxide
synthase; suppression of transcription factors such as NF-κB,
AP-1, and early growth response-1; inhibition of cyclooxyge-
nase-2 (COX-2) and lipoxygenase; suppression of adhesion
molecules; and inhibition of angiogenesis, invasion, and
metastasis. Limited data in humans have revealed that resver-
atrol is pharmacologically safe. As a nutraceutical, resveratrol is
commercially available in the USA and Europe in 50 µg to
60 mg doses. Currently, structural analogues of resveratrol with
improved bioavailability are being pursued as potential chemo-
preventive and therapeutic agents for cancer (73).
The ﬂavone quercetin (3,3′,4′,5,7-pentahydroxyﬂavone),
one of the major dietary ﬂavonoids, is found in a broad range
of fruits, vegetables, and beverages such as tea and wine, with
a daily intake in Western countries of 25–30 mg. The
antioxidant, anti-inﬂammatory, antiproliferative, and apopto-
tic effects of the molecule have been largely analyzed in cell
culture models, and it is known to block NF-κB activation. In
animal models, quercetin has been shown to inhibit inﬂam-
mation and prevent colon and lung cancer. A phase 1 clinical
trial indicated that the molecule can be safely administered
and that its plasma levels are sufﬁcient to inhibit lymphocyte
tyrosine kinase activity. Consumption of quercetin in onions
and apples was found to be inversely associated with lung
cancer risk in Hawaii. The effect of onions was particularly
strong against squamous cell carcinoma. In another study, an
increased plasma level of quercetin after a meal of onions was
accompanied by increased resistance to strand breakage in
lymphocytic DNA and decreased levels of some oxidative
metabolites in the urine (74).
The ﬂavonoid silymarin (silybin, isosilybin, silychristin,
silydianin, and taxifolin) is commonly found in the dried fruit
of the milk thistle plant Silybum marianum. Although
silymarin’s role as an antioxidant and hepatoprotective agent
is well known, its role as an anticancer agent is just emerging.
The anti-inﬂammatory effects of silymarin are mediated
through suppression of NF-κB-regulated gene products, in-
cluding COX-2, lipoxygenase (LOX), inducible NO synthase,
TNF, and IL-1. Numerous studies have indicated that
silymarin is a chemopreventive agent in vivo against various
carcinogens/tumor promoters, including UV light, 7,12-dime-
thylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-
acetate, and others. Silymarin has also been shown to
sensitize tumors to chemotherapeutic agents through down-
regulation of the MDR protein and other mechanisms. It
binds to both estrogen and androgen receptors and down-
regulates prostate speciﬁc antigen. In addition to its chemo-
preventive effects, silymarin exhibits activity against tumors
(e.g., prostate and ovary) in rodents. Various clinical trials
have indicated that silymarin is bioavailable and pharmaco-
logically safe. Studies are now in progress to demonstrate the
clinical efﬁcacy of silymarin against various cancers (75).
The ﬂa vonoid indole-3-carbinol (I3C) is present in
vegetables such as cabbage, broccoli, brussels sprout, cauli-
ﬂower, and daikon artichoke. The hydrolysis product of I3C
metabolizes to a variety of products, including the dimer 3,3′ -
diindolylmethane. Both I3C and 3,3′-diindolylmethane exert
a variety of biological and biochemical effects, most of which
appear to occur because I3C modulates several nuclear
transcription factors. I3C induces phase 1 and phase 2
enzymes that metabolize carcinogens, including estrogens.
I3C has also been found to be effective in treating some cases
of recurrent respiratory papillomatosis and may have other
clinical uses (76).
Sulforaphane (SFN) is an isothiothiocyanate found in
cruciferous vegetables such as broccoli. Its chemopreventive
effects have been established in both in vitro and in vivo
studies. The mechanisms of action of SFN include inhibition
of phase 1 enzymes, induction of phase 2 enzymes to detoxify
carcinogens, cell-cycle arrest, induction of apoptosis, inhibi-
tion of histone deacetylase, modulation of the MAPK
pathway, inhibition of NF-κB, and production of ROS.
Preclinical and clinical studies of this compound have
suggested its chemopreventive effects at several stages of
carcinogenesis. In a clinical trial, SFN was given to eight
healthy women an hour before they underwent elective
redu ction mammoplasty. Induction in NAD(P)H/quinone
oxidoreductase and heme oxygenase-1 was observed in the
breast tissue of all patients, indicating the anticancer effect of
Teas and Spices
Spices are used all over the world to add ﬂavor, taste,
and nutritional value to food. A growing body of research has
Fig. 9. Phytochemicals derived from fruits, vegetables, spices, condiments and cereals with potential to prevent cancer. 1 diosgenin, 2
glycyrrhizin, 3 glycyrrhetinic acid, 4 18-β-glycyrrhetinic acid, 5 oleandrin, 6 oleanolic acid, 7 betulinic acid, 8 lupeol, 9 guggulsterone, 10
celastrol, 11 ursolic acid, 12 acetyl-11-keto-β-boswellic acid, 13 1’-actoxychavicol acetate, 14 α-lipoic acid 15 yakuchinone A, 16 yakuchinone B,
17 curcumin, 18 gingerol, 19 resveratrol, 20 piceatannol 21 genistein, 22 capsaicin, 23 dibenzoylmethane, 24 piperine, 25 kahweol, 26 indiruibin-
3’-monoxime, 27 caffeic acid phenethyl ester, 28 emodin, 29 eugenol, 30 linalol, 31 quinic acid, 32 garcinol, 33 sesamin, 34 theaﬂavin-3,3’-
digallate, 35 sanguinarine, 36 silymarin, 37 mangostin, 38 mangiferin, 39 butein, 40 berberine, 41 glabridin, 42 myricetin,
43 carnosol, 44
β-lapachone, 45 evodiamine, 46 wogonin, 47 apigenin, 48 (-)-epigatechin, 49 tanshinones IIA, 50 tanshinones I, 51 (-)-epicatechin gallate, 52
epigallocatechin gallate, 53 carnosol, 54 zerumbone, 55 sulforaphane, 56 phytic acid, 57 allicin, 58 benzyl isothiocyanate, 59 baicalin, 60 ascorbic
acid, 61 anethole, 62 indole 3-carbinol, 63 phenyl isothiocyanate, 64 thymoquinone, 65 plumbagin, 66 γ-tocotrienol, 67 lutein, 68 β-
cryptoxanthine, 69 β-carotene, 70 lycopene, 71 α-tocoperol.
2106 Anand et al.
14 15 16 17 18
19 20 21 22 23 24
25 26 27 28 29 30 31
32 33 34 35 36
37 38 39 40 41
42 43 44 45 46 47 48
OH O OH
2107Cancer Prevention Requires Major Lifestyle Changes
demonstrated that phytochemicals such as catechins (green
tea), curcumin (turmeric), diallyldisulﬁde (garlic), thymoqui-
none (black cumin) capsaicin (red chili), gingerol (ginger),
anethole (licorice), diosgenin (fenugreek) and eugenol (clove,
cinnamon) possess therapeutic a nd preventive potential
against cancers of various anatomical origins. Other phyto-
chemicals with this potential include ellagic acid (clove),
ferulic acid (fennel, mustard, sesame), apigenin (coriander,
parsley), betulinic acid (rosemary), kaempferol (clove, fenu-
greek), sesamin (sesame), piperine (pepper), limonene (rose-
mary), and gambogic acid (kokum). Below is a description of
some important phytochemicals associated with cancer.
More than 3,000 studies have shown that catechins
derived from green and black teas have potential against
various cancers. A limited amount of data are also available
from green tea polyphenol chemoprevention trials. Phase 1
trials of healthy volunteers have deﬁned the basic biodistri-
bution patterns, pharmacokinetic parameters, and prelimi-
nary safety proﬁles for short-term oral administration of
various green tea preparations. The consumption of green tea
appears to be relatively safe. Among patients with established
premalignant conditions, green tea derivatives have shown
potential efﬁcacy against cervical, prostate, and hepatic
malignancies without inducing major toxic effects. One novel
study determined that even persons with solid tumors could
safely consume up to 1 g of green tea solids, the equivalent of
approximately 900 ml of green tea, three times daily. This
observation supports the use of green tea for both cancer
prevention and treatment (78).
Curcumin is one of the most extensively studied com-
pounds isolated from dietary sources for inhibition of
inﬂammation and cancer chemoprevention, as indicated by
almost 3000 published studies. Studies from our laboratory
showed that curcumin inhibited NF-κB and NF-κB-regulated
gene expression in various cancer cell lines. In vitro and in
vivo studies showed that this phytochemical inhibited inﬂam-
mation and carcinogenesis in animal models, including breast,
esophageal, stomach, and colon cancer models. Other studies
showed that curcumin inhibited ulcerative proctitis and
Crohn’s disease, and one showed that curcumin inhibited
ulcerative colitis in humans. Another study evaluated the
effect of a combination of curcumin and piperine in patients
with tropical pancreatitis. One study conducted in patients
with familial adenomatous polyposis showed that curcumin
49 50 51 52 53 54
55 56 57 58 59 60
61 62 63 64 65 66
67 68 69
Fig. 9. (continued)
2108 Anand et al.
has a potential role in inhibiting this condition. In that study,
all ﬁve patients were treated with curcumin and quercetin for
a mean of 6 months and had a decreased polyp number
(60.4%) and size (50.9%) from baseline with minimal adverse
effects and no laboratory-determined abnormalities.
The pharmacodynamic and pharmacokinetic effects of
oral Curcuma extract in patients with colorectal cancer have
also been studied. In a study of patients with advanced
colorectal cancer refractory to standard chemotherapies, 15
patients received Curcuma extract daily for up to 4 months.
Results showed that oral Curcuma extract was well tolerated,
and dose-limiting toxic effects were not observed. Another
study showed that in patients with advanced c olorectal
cancer, a daily dose of 3.6 g of curcumin engendered a 62%
decrease in inducible prostaglandin E2 production on day 1
and a 57% decrease on day 29 in blood samples taken 1 h
after dose administration.
An early clinical trial with 62 cancer patients with
external cancerous lesions at various sites (breast, 37; vulva,
4; oral, 7; skin, 7; and others, 11) reported reductions in the
sense of smell (90% of patients), itching (almost all patients),
lesion size and pain (10% of patients), and exudates (70% of
patients) after topical application of an ointment containing
curcumin. In a phase 1 clinical trial, a daily dose of 8,000 mg
of curcumin taken by mouth for 3 months resulted in
histologic improvement of precancerous lesions in patients
with uterine cervical intraepithelial neoplasm (one of four
patients), intestinal metaplasia (one of six patients), bladder
cancer (one of two patients), and oral leukoplakia (two of
Results from another study conducted by our group
showed that curcumin inhibited constitutive activation of NF-
κB, COX-2, and STAT3 in peripheral blood mononuclear
cells from the 29 multiple myeloma patients enrolled in this
study. Curcumin was given in doses of 2, 4, 8, or 12 g/day
orally. Treatment with curcumin was well tolerated with no
adverse events. Of the 29 patients, 12 underwent treatment
for 12 weeks and 5 completed 1 year of treatment with stable
disease. Other studies from our group showed that curcumin
inhibited pancreatic cancer. Curcumin down-regulated the
expression of NF-κB, COX-2, and phosphorylated STAT3 in
peripheral blood mononuclear cells from patients (most of
whom had baseline levels considerably higher than those
found in healthy volunteers). These studies showed that
curcumin is a potent anti-inﬂammatory and chemopreventive
agent. A detailed description of curcumin and its anticancer
properties can be found in one of our recent reviews (79).
Diallyldisulﬁde, isolated from garlic, inhibits the growth
and proliferation of a number of cancer cell lines including
colon, breast, glioblastoma, melanoma, and neuroblastoma
cell lines. Recent studies showed that this compound induces
apoptosis in Colo 320 DM human colon cancer cells by
inhibiting COX-2, NF-κB, and ERK-2. It has been shown to
inhibit a number of cancers including dimethylhydrazine-induced
colon cancer, benzo[a]pyrene-induced neoplasia, and glutathione
S-transferase activity in mice; benzo[a]pyrene-induced skin
carcinogenesis in mice; N-nitrosomethylbenzylamine-induced
esophageal cancer in rats; N-nitrosodiethylamine-induced forest-
omach neoplasia in female A/J mice; aristolochic acid-induced
forestomach carcinogenesis in rats; diethylnitrosamine-induced
glutathione S-transferase positive foci in rat liver; 2-amino-
esis in rats; and diethylnitrosamine-induced liver foci and
hepatocellular adenomas in C3H mice. Diallyldisulﬁde has
also been shown to inhibit mutagenesis or tumorigenesis
induced by vinyl carbamate and N-nitrosodimethylamine;
aﬂatoxin B1-induced and N-nitrosodiethylamine-induced
liver preneoplastic foci in rats; arylamine N-acetyltransfer-
ase activity and 2-aminoﬂuorene-DNA adducts in hu man
promyelocytic l eukemia cells; DMBA-induced mouse skin
tumors; N-nitrosomethylbenzylamine-induced mutation in
rat esophagus; and diethylstilbesterol-induced DNA ad-
ducts in the breasts of female ACI rats.
Diallyldisulﬁde is believed to bring about an anticarcino-
gen ic effect through a number of mechanisms, s uch as
scavenging of radicals; increasing gluathione levels; increasing
the activities of enzymes such as glutathione S-transferase and
catalase; inhibiting cytochrome p4502E1 and DNA repair
mechanisms; and preventing chromosomal damage (80).
The chemotherapeutic and chemoprotective agents from
black cumin include thymoquinone (TQ), dithymoquinone
(DTQ), and thymohydroquinone, which are present in the oil
of this seed. TQ has antineoplastic activity against various
tumor cells. DTQ also contributes to the chemotherapeutic
effects of Nigella sativa. In vitro study results indicated that
DTQ and TQ are equally cytotoxic to several parental cell
lines and to their corresponding multidrug-resistant human
tumor cell lines. TQ induces apoptosis by p53-dependent and
p53-independent pathways in cancer cell lines. It also induces
cell-cycle arrest and modulates the levels of inﬂammatory
mediators. To date, the chemotherapeutic potential of TQ has
not been tested, but numerous studies have shown its
promising anticancer effects in animal models. TQ suppresses
carcinogen-induced forestomach and skin tumor formation in
mice and acts as a chemopreventive agent at the early stage
of skin tumorigenesis. Moreover, the combination of TQ and
clinically used anticancer drugs has been shown to improve
the drug’s therapeutic index, prevents nontumor tissues from
sustaining chemotherapy-induced damage, and enhances the
antitumor activity of drugs such as cisplatin and ifosfamide. A
very recent report from our own group established that TQ
affects the NF-κB signaling pathway by suppressing NF-κB
and NF-κB-regulated gene products (81).
The phenolic compound capsaicin (t8-methyl-N-vanillyl-
6-nonenamide), a component of red chili, has been exten-
sively studied. Although capsaicin has been suspected to be a
carcinogen, a considerable amount of evidence suggests that
it has chemopreventive effects. The antioxidant, anti-inﬂamma-
tory, and antitumor properties of capsaicin have been estab-
lished in both in vitro and in vivo systems. For example, showed
that capsaicin can suppress the TPA-stimulated activation of
NF-κB and AP-1 in cultured HL-60 cells. In addition, capsaicin
inhibited the constitutive activation of NF-κB in malignant
2109Cancer Prevention Requires Major Lifestyle Changes
melanoma cells. Furthermore, capsaicin strongly suppressed
the TPA-stimulated activation of NF-κB and the epidermal
activation of AP-1 in mice. Another proposed mechanism of
action of capsaicin is its interaction with xenobiotic metaboliz-
ing enzymes, involved in the activation and detoxiﬁcation of
various chemical carcinogens and mutagens. Metabolism of
capsaicin by hepatic enzymes produces reactive phenoxy
radical intermediates capable of binding to the active sites of
enzymes and tissue macromolecules.
Capsaicin can inhibit platelet aggregation and suppress
calcium-ionophore–stimulated proinﬂammatory responses,
such as the generation of superoxide anion, phospholipase
A2 activity, and membrane lipid per oxidation in macro-
phages. It acts as an antioxidant in various organs of
laboratory animals. Anti-inﬂammatory properties of capsaicin
against carcinogen-induced inﬂammation have also been
reported in rats and mice. Capsaicin has exerted protective
effects against ethanol-induced gastric mucosal injury, hem-
orrhagic erosion, lipid peroxidation, and myeloperoxidase
activity in rats that was associated with suppression of COX-
2. While lacking intrinsic tumor-promoting activity, capsaicin
inhibited TPA-promoted mouse skin papillomagenesis (82).
Gingerol, a phenolic substance mainly present in the spice
ginger (Zingiber officinale Roscoe), has diverse pharmacologic
effects including antioxidant, antiapoptotic, and anti-inﬂam-
matory effects. Gingerol has been shown to have anticancer
and chemopreventive properties, and the proposed mecha-
nisms of action include the inhibition of COX-2 expression by
blocking of the p38 MAPK–NF-κB signaling pathway. A
detailed report on the cancer-preventive ability of gingerol
was presented in a recent review by Shukla and Singh (83).
Anethole, the principal active component of the spice
fennel, has shown anticancer activity. In 1995, Al-Harbi et al.
(84) studied the antitumor activity of anethole against Ehrlich
ascites carcinoma induced in a tumor model in mice. The
study revealed that anethole increased survival time, reduced
tumor weight, and reduced the volume and body weight of the
EAT-bearing mice. It also produced a signiﬁcant cytotoxic
effect in the EAT cells in the paw, reduced the levels of nucleic
acids and MDA, and increased NP-SH concentrations.
The histopathological changes observed after treatment
with anethole were comparable to those after treatment with
the standard cytotoxic drug cyclophosphamide. The frequency
of micronuclei occurrence and the ratio of polychromatic
erythrocytes to normochromatic erythrocytes showed anethole
to be mitodepressive and nonclastogenic in the femoral cells of
mice. In 1996, Sen et al., (85)studiedtheNF-κB inhibitory
activity of a derivative of anethole and anetholdithiolthione.
Their study results showed that anethole inhibited H
phorbol myristate acetate or TNF alpha induced NF-κB
activation in human jurkat T-cells (86) studied the anticarcino-
genic activity of anethole trithione against DMBA induced in a
rat mammary cancer model. The study results showed that this
phytochemical inhibited mammary tumor growth in a dose-
Nakagawa and Suzuki (87) studied the metabolism and
mechanism of action of trans-anethole (anethole) and the
estrogenlike activity of the compound and its metabolites in
freshly isolated rat hepatocytes and cultured MCF-7 human
breast cancer cells. The results suggested that the biotrans-
formation of anethole induces a cytotoxic effect at higher
concentrations in rat hepatocytes and an estrogenic effect at
lower concentrations in MCF-7 cells on the basis of the
concentrations of the hydroxylated intermediate, 4OHPB.
Results from preclinical studies have suggested th at the
organosulfur compound anethole dithiolethione may be an
effective chemopreventive agent against lung cancer. Lam et
al,(88) conducted a phase 2b trial of anethole dithiolethione
in smoker s with bronchial dysplasia. The results of this
clinical trial suggested that anethole dithiolethione is a
potentially efﬁcacious chemopreventive agent against lung
Diosgenin, a steroidal saponin present in fenugreek, has
been shown to suppress inﬂammation, inhibit proliferation,
and induce apoptosis in various tumor cells. Research during
the past decade has shown that diosgenin suppresses prolif-
eration and induces apoptosis in a wide variety of cancer cells
lines. Antiproliferative effects of diosgenin are mediated
through cell-cycle arrest, disruption of Ca
activation of p53, release of apoptosis-inducing factor, and
modulation of caspase-3 activity. Diosgenin also inhibits
azoxymethane-induced aberrant colon crypt foci, has been
shown to inhibit intestinal inﬂ ammation, and modulates the
activity of LOX and COX-2. Diosgenin has also been shown
to bind to the chemokine receptor CXCR3, which mediates
inﬂammatory responses. Results from our own laboratory
have shown that diosgenin inhibits osteoclastogenesis, cell
invasion, and cell proliferation through Akt down-regulation,
IκB kinase activation, and NF-κB-regulated gene expression
Eugenol is one of the active components of cloves.
Studies conducted by Ghosh et al.(90) showed that eugenol
suppressed the proliferation of melanoma cells. In a B16
xenograft study, eugenol treatment produced a signiﬁcant
tumor growth delay, an almost 40% decrease in tumor size,
and a 19% increase in the median time to end point. Of more
importance, 50% of the animals in the control group died of
metastatic growth, whereas none in the eugenol treatment
group showed any signs of cell invasion or metastasis. In 1994,
Sukumaran et al.(91) showed that eugenol DMBA induced
skin tumors in mice. The same study showed that eugenol
inhibited superoxide formation and lipid peroxidation and the
radical scavenging activity that may be responsible for its
chemopreventive action. Studies conducted by Imaida et al.
(92) showed that eugenol enhanced the development of 1,2-
dimethylhydrazine-induced hyperplasia and papillomas in the
forestomach but decreased the incidence of 1-methyl-1-nitro-
sourea-induced kidney nephroblastomas in F344 male rats.
Another study conducted by Pisano et al.(93) demon-
strated that eugenol and related biphenyl (S)-6,6′-dibromo-
2110 Anand et al.
dehydrodieugenol elicit speciﬁc antiproliferative activity on
neuroectodermal tumor cells, partially triggering apoptosis. In
2003, Kim et al.(94) showed that eugenol suppresses COX-2
mRNA expression (one of the main genes implicated in the
processes of inﬂammation and carcinogenesis) in HT-29 cells
and lipopolysaccharide-stimulat ed mouse macrophage
RAW264.7 cells. Another study by Deigner et al.(95) showed
that 1′-hydroxyeugenol is a good inhibitor of 5-lipoxygenase
and Cu(2+)-mediated low-density lipoprotein oxidation. The
studies by Rompelberg et al.(96)showedthatin vivo
treatment of rats with eugenol reduced the mutagenicity of
benzopyrene in the Salmonella typhimurium mutagenicity
assay, whereas in vitro treatment of cultured cells with
eugenol increased the genotoxicity of benzopyrene.
The major wholegrain foods are wheat, rice, and maize;
the minor ones are barley, sorghum, millet, rye, and oats.
Grains form the dietary staple for most cultures, but most are
eaten as reﬁned-grain products in Westernized countries (97).
Whole grains contain chemopreventive antioxidants such as
vitamin E, tocotrienols, phenolic acids, lignans, and phytic
acid. The antioxidant content of whole grains is less than that
of some berries but is greater than that of common fruits or
vegetables (98). The reﬁning process concentrates the carbo-
hydrate and reduces the amount of other macronutrients,
vitamins, and minerals because the outer layers are removed.
In fact, all nutrients with potential preventive actions against
cancer are reduced. For example, vitamin E is reduced by as
much as 92% (99).
Wholegrain intake was found to reduce the risk of several
cancers including those of the oral cavity, pharynx, esophagus,
gallbladder, larynx, bowel, colorectum, upper digestive tract,
breasts, liver, endometrium, ovaries, prostate gland, bladder,
kidneys, and thyroid gland, as well as lymphomas, leukemias,
and myeloma (100,101). Intake of wholegrain foods in these
studies reduced the risk of cancers by 30–70% (102).
How do whole grains reduce the risk of cancer? Several
potential mechanisms have been described. Fo r instance,
insoluble ﬁbers, a major constituent of whole grains, can reduce
the risk of bowel cancer (103). Additionally, insoluble ﬁber
undergoes fermentation, thus producing short-chain fatty acids
such as butyrate, which is an important suppressor of tumor
formation (104). Whole grains also mediate favorable glucose
response, which is protective against breast and colon cancers
(105). Also, several phytochemicals from grains and pulses
were reported to have chemopreventive action against a wide
variety of cancers. For example, isoﬂavones (including daid-
zein, genistein, and equol) are nonsteroidal diphenolic com-
pounds that are found in leguminous plants and have
antiproliferative activities. Findings from several, but not all,
studies have shown signiﬁcant correlations between an
isoﬂavone-rich soy-based diet and reduced incidence of cancer
or mortality from cancer in humans. Our laboratory has shown
that tocotrienols, but not tocopherols, can suppress NF-κ
activation induced by most carcinogens, thus leading to
suppression of various genes linked with proliferation, surviv-
al, invasion, and angiogenesis of tumors (106).
Observational studies have suggested that a diet rich in soy
isoﬂavones (such as the typical Asian diet) is one of the most
signiﬁcant contributing factors for the lower observed incidence
and mortality of prostate cancers in Asia. On the basis of
ﬁndings about diet and of urinary excretion levels associated
with daidzein, genistein, and equol in Japanese subjects
compared with ﬁndings in American or European subjects,
the isoﬂavonoids in soy products were proposed to be the
agents responsible for reduced cancer risk. In addition to its
effect on breast cancer, genistein and related isoﬂavones also
inhibit cell growth or the development of chemically induced
cancers in the stomach, bladder, lung, prostate, and blood (107).
Although controversial, the role of vitamins in cancer
chemoprevention is being evaluated increasingly. Fruits and
vegetables are the primary dietary sources of vitamins except
for vitamin D. Vitamins, especially vitamins C, D, and E, are
reported to have cancer chemopreventive activity without
Epidemiologic study ﬁndings suggest that the anticancer/
chemopreventive effects of vitamin C against various types of
cancers correlate with its antioxidant activities and with the
inhibition of inﬂammation and gap junction intercellular
communication. Findings from a recent epidemiologic study
showed that a high vitamin C concentration in plasma had an
inverse relationship with cancer-related mortality. In 1997,
expert panels at the World Cancer Research Fund and the
American Institute f or Cancer Research estimated t hat
vitamin C can reduce the risk of cancers of the stomach,
mouth, pharynx, esophagus, lung, pancreas, and cervix (108).
The protective effects of vitamin D result from its role as
a nuclear transcription factor that regulates cell grow th,
differentiation, apoptosis, and a wide range of cellular
mechanisms central to the development of cancer (109).
There is extensive evidence suggesting that regular
physical exercise may reduce the incidence of various cancers.
A sedentary lifestyle has been associated with most chronic
illnesses. Physical inactivity has been linked with increased
risk of cancer of the breast, colon, prostate, and pancreas and
of melanoma (110). The increased risk of breast cancer
among sedentary women that has been shown to be due to
lack of exercise has been associated with a higher serum
concentration of estradiol, lower concentration of hormone-
binding globulin, larger fat masses, and higher serum insulin
levels. Physical inactivity can also increase the risk of colon
cancer (most likely because of an increase in GI transit time,
thereby increasing the duration of contact with potential
carcinogens), increase the circulating levels of insulin (pro-
mote proliferation of colonic epithelial cells), alter prosta-
glandin levels, depress the immune function, and modify bile
acid metabolism. Additionally, men with a low level of
physical activity and women with a larger body mass index
were more likely to have a Ki-ras mutation in their tumors,
which occurs in 30–50% of colon cancers. A reduction of
almost 50% in the incidence of colon cancer was observed
among those with the highest levels of physical activity (111).
Similarly, higher blood testosterone and IGF-1 levels and
suppressed immunity due to lack of exercise may increase the
2111Cancer Prevention Requires Major Lifestyle Changes
incidence of prostate cancer. On e study indicated that
sedentary men had a 56% and women a 72% higher
incidence of melanoma than did those exercising 5–7 days
per week (112).
Fasting is a type of caloric restriction (CR) that is
prescribed in most cultures. Perhaps one of the ﬁrst reports
that CR can inﬂuence cancer incidence was published in 1940
on the formation of skin tumors and hepatoma in mice (113,
114). Since then, several reports on this subject have been
published (115, 116). Dietary restriction, especially CR, is a
major modiﬁer in experimental carcinogenesis and is known
to signiﬁcantly decrease the incidence of neoplasms. Gross
and Dreyfuss reported that a 36% restriction in caloric intake
dramatically decreased radiation-induced solid tumors and/or
leukemias (117, 118). Yoshida et al.(119) also showed that
CR reduces the incidence of myeloid leukemia induced by a
single treatment with whole-body irradiation in mice.
How CR reduces the incidence of cancer is not fully
understood. CR in rodents decreases the levels of plasma
glucose and IGF-1 and postpones or attenuates cancer and
inﬂammation without irreversible adverse effects (120). Most
of the studies done on the effect of CR in rodents are long-
term; however, that is not possible in humans, who routinely
practice transient CR. The effect that transient CR has on
cancer in humans is unclear.
On the basis of the studies described above, we propose
a unifying hypothesis that all lifestyle factors that cause
cancer (carcinogenic agen ts) and all agents that prev ent
cancer (chemopreventive agents) are linked through chronic
inﬂammation (Fig. 10). The fact that chronic inﬂammation is
closely linked to the tumorigenic pathway is evident from
numerous lines of evidence.
First, inﬂammatory markers such as cytokines (such as
TNF, IL-1, IL-6, and chemokines), enzymes (such as COX-2,
5-LOX, and matrix meta lloproteinase-9 [MMP-9]), and
adhesion molecules (such as intercellular adhesion molecule
1, endothelium leukocyte adhesion molecule 1, and vascular
cell adhesion molecule 1) have been closely linked with
tumorigenesis. Second, all of these inﬂammatory gene
products have been shown to be regulated by the nuclear
transcription factor, NF-κB. Third, NF-κB has been shown to
control the expression of other gene products linked with
Fig. 10. Carcinogens activate and chemopreventive agents suppress NF-κB activation, a major mediator of inﬂammation.
2112 Anand et al.
tumorigenesis such as tumor cell survival or antiapoptosis
(Bcl-2, Bcl-xL, IAP-1, IAP-2, XIAP, survivin, cFLIP, and
TRAF-1), proliferation (such as c-myc an d cyclin D1),
invasion (MMP-9), and angiogenesis (vascular endothelial
growth factor). Fourth, in most cancers, chronic inﬂammation
Fifth, most carcinogens and other risk factors for cancer,
including cigarette smoke, obesity, alcohol, hyperglycemia,
infectious agents, sunlight, stress, food carcin ogens, and
environmental pollutants, have been shown to activate NF-
κB. Sixth, constitutive NF-κB activation has been encountered
in most types of cancers. Seventh, most chemotherapeutic
agents and γ-radiation, used for the treatment of cancers, lead
to activation of NF-κB. Eighth, activation of NF-κB has been
linked with chemoresistance and radioresistance. Ninth, sup-
pression of NF-κB inhibits the proliferation of tumors, leads to
apoptosis, inhibits i nvasion, and suppresses angiogenesis.
Tenth, polymorphisms of TNF, IL-1, IL-6, and cyclin D1 genes
encountered in various cancers are all regulated by NF-κB.
Also, mutations in genes encoding for inhibitors of NF-κB
have been found in certain canc ers. Ele venth, almost all
chemopreventive agents described above have been shown to
suppress NF-κB activation. In summary, this review outlines
the preventability of cancer based on the major risk factors for
cancer. The percentage of cancer-related deaths attributable to
diet and tobacco is as high as 60–70% worldwide.
This research was supported by The Clayton Foundation
for Research (to B.B.A.).
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