Note: Descriptions are shown in the official language in which they were submitted.
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EXTRACTS OF ORANGE PEEL FOR PREVENTION
AND TREATMENT OF CANCER
Background of the Invention
Naturally occurring non-nutritive agents present in
plants such as flavonoids, phenolic compounds, glucosinulates,
terpenes and many others are believed to have disease
preventive properties. Diets containing some of these
substances have been shown to be protective against diseases
such as colon and breast cancer in animals (Kuo, S.M. 1997.
Clin. Rev. Oncogenesis 8:47-69; Verhoeven et al. 1996. Cancer
Epid. Biomark. Prev. 5:733-748; Bradlow et al. 1991.
Carcinogenesis 12:1571-1574; Lamartiniere et al. 1995. Proc.
Soc. Exp. Biol. Med. 208:120-123). The clinical relevance of
such natural phytochemicals is dependent on extrapolation from
epidemiological data and from experiments in animal models of
diseases of interest.
Purified flavenoid compounds isolated from citrus juice
have been tested individually for their effects on
carcinogenesis, tumor cell growth and invasion of tumor cells
into normal cells (Attaway, J.A. 1994. In: Food
Phytochemicals for Cancer Prevention, ACS Symposia Series
#546, Huang et al. Eds., pp. 240-248). In particular the
polymethyoxylated flavenoids, tangeretin and nobeletin, were
shown to have anti-carcinogenic activity.
Extracts of bitter-orange peel are used as an herbal
drug (Bisset, N.G. 1994. Herbal Drugs and
Phytopharmaceuticals, CRC Press: Boca Raton) Conditions
treated include loss of appetite and dyspeptic complaints.
The main components of the extract include limonene and
flavonoids such as neohesperidin and naringin.
Several patents disclose the use of various
phytochemicals in combination with orange peel extract or
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dried orange peel. CN 1200277 describes use of a composition
composed of 16 plant components, one of which is dried orange
peel, for treatment of psychosis and nervous system disease.
CN 1116945 describes the use of orange peel along with several
other natural products in a capsule form to sooth the liver,
nourish the stomach, remove stasis, stop pain and cure various
gastric diseases. CN 1111134 discloses an oral liquid
containing orange peel, among other things, for treatment of
neurastenia, chronic bronchitis, asthma, coronary heart
disease, high blood lipid levels, hepatitis, cytopenia,
senility and immune dysfunction. CN 1106673 is a patent for
a disease-preventing nutrient tea that is produced from a
variety of products, including soaked, crushed orange peel.
CN 1077124 describes a Chinese herb preparation for treatment
of iron-deficiency anemia that is composed of a number of
ingredients, including dried orange peel. Finally, a Japanese
patent (JP 57156761) discloses a heat-generating pad for
orthopedic diseases that contains extracts and powders of many
plants, including orange peel.
It has now been found that an extract of orange peel has
biological activity as a treatment and preventative agent for
cancer.
Summary of the Invention
An object of the present invention is an extract of
orange peel which comprises 41,5,6,7,8-pentamethoxyflavone and
3',41,5,6,7,8-hexamethoxyflavone. The composition may further
comprise other polymethoxylated flavones.
Another object of the present invention is a composition
which comprises an extract of orange peel and rosemary
extract, a Mexican Bamboo extract, a Huzhang extract,
resveratrol, a black tea extract, and/or a hydroxylated or
methoxylated resveratrol analog.
Another object of the present invention is to provide
a method for inhibiting tumor cell growth in an animal
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comprising administering to an animal an orange peel extract
which is administered alone or in combination with rosemary
extract, a Mexican Bamboo extract, a Huzhang extract,
resveratrol, a black tea extract, and/or a hydroxylated or
methoxylated resveratrol analog.
Another object of the present invention is to provide
a method for preventing or treating cancer in an animal which
comprises administering to an animal an effective amount of an
orange peel extract which is administered alone or in
combination with rosemary extract, a Mexican Bamboo extract,
a Huzhang extract, resveratrol, a black tea extract, and/or a
hydroxylated or methoxylated resveratrol analog.
Detailed Description of the Invention
Unlike many phytochemicals, orange peel extract is lipid
soluble, a property which is desirable in many drug products
because passage across biological membranes, and ultimately
bioavailability, is enhanced. Orange peel and its extracts
have been used in a variety of herbal drug products in
combination with many different plant components and extracts.
However, none of the previous research on orange peel or its
extracts has examined or demonstrated activity against tumor
cell growth or cancer. It has now been shown that orange peel
extract inhibits tumor growth in vivo.
Orange peel extract is a mixture of highly bioactive and
organic soluble, methylated flavonoids. An extract was
obtained from cold-pressed peel oil solids, a waste product
from the orange juice industry. The peel oil solids were
dissolved in warm ethanol and, after several repeated washes,
became a standardized product, with a reproducible amount of
flavonoids. The extract comprises a mixture of various
analogs and homologs of methylated flavonoids.
Experiments were performed to isolate and identify
components in the orange peel extract. Methylated flavonoids
from the orange peel extract were analyzed by either reverse-
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phase or normal-phase high performance liquid chromatography
(HPLC). During normal phase HPLC the conditions included use
of a silica gel HPLC column (MacMod Analytical Co., Chadds
Ford, PA) of dimensions 4.6 mm i.d. x 25 cm length and a
solvent gradient that started at 90% hexane and went to 90%
chloroform in 20 minutes with a final hold at 90% chloroform
for an additional 20 minutes. Separated components or peaks
were then identified using HPLC coupled with mass spectrometry
(HPLC-MS). Atmospheric pressure chemical ionization mass
spectrometry was used for molecular weight determinations.
HPLC-MS techniques such as particle beam (EI) introduction was
used to produce standard fragmentation patterns of the
methylated flavonoids. Standards for many of the compounds
were obtained from the Florida Department of Citrus. Using
these techniques the following components were identified:
5,6,7,3',41-pentamethoxyflavone (also known as sinensetin),
5,6,7,8,3',4'-hexamethoxyflavone (also known as nobeletin),
5,6,7,8,4'-pentamethoxyflavone (also known as tangeretin), 5-
hydroxy-6,7,8,31,4'-pentamethoxyflavone (also known as
auranetin), 5-hydroxy-7,8,3',4'-methoxyflavone, 5,7-hydroxy-
6,8,3',4'-methoxyflavone, 5,7,8,3',4'-pentamethoxyflavone,
5,7,8,41-methoxyflavone, 3,5,6,7,8,3',4'-methoxyflavone, 5-
hydroxy-3,6,7,8,3',4'-methoxyflavone, 5-hydroxy-6,7,8,4'-
methoxyflavone, 5,6,7,4'-methoxyflavone, 7-hydroxy-
3,5,6,8,3',4'-methoxyflavone, and 7-hydroxy-3,5,6,3',4'-
methoxyflavone.
The in vivo tumor inhibitory effects of the complete
(including all 14 identified compounds) orange peel extract
was tested in an orthotransplant model (Telang, N.T. et al.
1990. Cell Regulat. 1:863-872). Mice were transplanted with
oncogene-expressing, preneoplastic breast epithelial cells.
Mice were then divided into groups with the control group fed
AIN-76A diet alone. Another group of mice was fed AIN-76A
diet supplemented with 5000 ppm orange peel extract. After 12
weeks of continuous feeding, all mice in the control group
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exhibited palpable tumor formation at the transplant sites
(100% tumor incidence). In contrast, the group fed diet
supplemented with the orange peel extract had a 0% tumor
incidence (0/5 mice). Weight gains in the groups were
5 comparable indicating that the orange peel extract had little
to no systemic toxicity.
The orange peel extract was then tested in an in vivo
model for colon cancer. Female CF-1 mice were injected with
azoxymethane (AOM) once a week for four weeks at increasing
doses (5, 10, 10 and 10 mg/kg) . Orange peel extract was
administered in the diet (0.2%) starting two weeks before the
first AOM injection, during and continuing until the end of
the experiment at 24 weeks. At week 24, the mice were given
one last dose of AOM (10 mg/kg) . The mice were then
sacrificed and their colons removed (from anus to caecum).
The colons were opened longitudinally, rinsed with normal
saline, and stapled to a plastic sheet. The colon samples
were placed in a 10% neutral buffered formalin solution for 24
hours. The entire colon was stained with 0.2% methylene blue
dissolved in phosphate buffered saline for 20 minutes. The
whole mount of colon samples were then examined using light
microscopy for the presence of aberrant crypt (AC) or aberrant
crypt foci (ACF). Both ACF and AC are biomarkers for colon
cancer. Cancer prevention diets have been shown to reduce
formation of ACF and AC. Mice fed nordihydroxyguaiaretic acid
(NDGA) in the diet (0.2%) were used as controls. The results
are shown below in Table 1.
Table 1
Effect of Feeding Orange Peel Extract on AOM-Induced
Formation of Aberrant Crypt Foci (ACF) in Mice
Lesion Negative Positive 0.2% NDGA 0.2%
Control Control Orange
Peel
ACF/colon 0 5.2 1.2 2.7 0.9 2.7 0.8
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AC/colon 0 37 5.9 9.4 2.2 12.6 2.8
AC/ACF 0 7.1 3.5 4.7
ACF: 0 15.0 2.5 6.8 1.5 6.4 1.4
1
AC/colon
ACF: 0 5.5 1.2 1.0 0.3 2.0 0.3
2
AC/colon
ACF: 0 1.0 0.4 0.2 0.2 0.2 0.2
3
AC/colon
ACF: 0 1.0 0.4 0 0.2 0.2
4
AC/colon
ACF: 0 0.2 0.2 0 0
5
AC/colon
ACF: 0 0.3+0.3 0 0.2 0.23
6
AC/colon
ACF: 0 0.2 0.2 0 0
7
AC/colon
There was a 48% and 48% inhibition of the number of ACF per
colon with NDGA and orange peel extract treatment,
respectively. In addition, the ratio of AC/ACF was inhibited
by 51% and 34%, with NDGA and orange peel extract treatment,
respectively. These data demonstrate the efficacy of the
orange peel extract in this animal model of colon cancer.
In a similar experiment in the mouse colon cancer model,
CF-1 mice were injected with AOM (5, 10, 10 and 10 mg/kg)
starting at 6 weeks of age, once each week and then once at 37
weeks after the first dose of AOM. Throughout the treatment
period, mice received either an AIN 76A diet or test compound
in AIN 76A diet at 2 weeks before the first dose of AOM and
continuing until the end of the experiment. The test
compounds were NDGA (0.2%) and orange peel extract (0.2%).
Colon samples were again obtained at sacrifice, stored in 10%
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formalin phosphate buffer, and then colon tumor number was
determined. The results are shown in Table 2.
Table 2
Effect of Dietary Orange Peel Extract Treatment on AOM-
Induced Colon Tumorigenesis in Mice
Treatment Number of Body Colon Tumors Percent
Animals Weight Per Mouse Incidence
(g) (%)
no AOM 15 51.3 1.9 0 0
(negative
control)
AOM 27 46.7 1.9 0.52 0.12 44
0.2% NDGA 11 45.8 2.1 0.27 0.14 27
+ AOM
0.2% 17 46.7 2.2 0.29 0.11 29
Orange
Peel +
AOM
The data show that treatment with orange peel extract
inhibited tumor development in AOM-treated mice to the same
extent as the control comparison compound, NDGA, supporting
the efficacy of orange peel extract as an anti-tumorigenic
agent.
In addition to testing for the activity of the complete
orange peel extract, two of the identified extract components,
tangeretin and nobeletin, were tested for their combined
activity in a cell proliferation assay. The growth of W138
(normal) and W138VA (transformed) cells was tested in the
presence of a mixture of tangeretin and nobeletin. The dye
crystal violet was used for measuring growth of the cells.
Cells were treated with either tangeretin alone (0, 1, 5, 10,
20 or 50 g/ml), nobeletin alone (0, 1, 5, 10, 20 or 50 g/ml)
or a mixture of the two compounds at a total concentration of
the two flavenoids of 0, 1, 5, 10, 20 or 50 g/ml. When used
alone, tangeretin and nobeletin produced only marginal
effects to inhibit cell growth in transformed cells, even at
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the highest dose tested, and had no effect on normal cell
growth. In contrast, when administered as a mixture,
tangeretin and nobeletin showed synergistic activity, with
growth inhibition produced in transformed cells, in a dose
dependent manner. There was no appreciable effect of the
mixture on normal cell growth. These data confirm the results
of the experiment in whole animals where orange peel extract,
containing tangeretin and noveletin, had anti-tumorigenic
activity. Further, when an extract containing 30% of the
methylated flavenoids, including tangeretin and nobeletin was
tested in this same assay there were significant inhibitory
effects of cell proliferation at doses of 20 and 50 g/ml.
The range of doses of the extract tested was 0, 1, 5, 10, 20
and 50 g/ml. These data provide evidence for a synergistic
effect of the polymethylated flavonoids in arresting and
inhibiting the growth of tumor cells.
Experiments were also performed in a preclinical cell
culture model for human ductal breast carcinoma in situ
(DCIS). The human breast-derived preneoplastic cell line 184-
B5/HER expressed HER-2/neu, p53 and EGFR but not ER, therefore
resembling the clinical DCIS. Initial dose-response
experiments compared the growth inhibitory effect of orange
peel extract on the parental 184-B5 cells and the HER-2/neu
oncogene-expressing 184-B5/HER cells. Relative to parental
cells, orange peel extract was at least two times more
effective as a growth inhibitor for 184-B5/HER cells. Orange
peel extract at the maximum cytostatic dose of 100 ppm
accumulated the cells in the GO/G1 phase and inhibited the
S+G2/M phase of the cell cycle, leading to down-regulation of
cell cycle progression. This alteration in the cell cycle
progression resulted in a 5-fold increase in the GO/Gl: S+G2/M
ratio. Treatment of 184-B5/HER cells with 100 ppm orange peel
extract resulted in a 47.5% decrease in immunoreactivity to
phosphotyrosine (marker for tyrosine kinase activity) and a
157.7% increase in immunoreactivity to the cyclin dependent
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kinase inhibitor p16INK'. In addition, there was a selective
induction of apoptosis in 184-B5/HER cells but not in parental
184-B5 cells. Treatment of 184-B5/HER cells with 100 ppm
orange peel extract induced a 7.6-fold increase in sub G0/Gl
(apoptotic) population. Consistent with the induction of
apoptosis, immunoreactivity to anti-apoptotic Bcl-2 was
decreased by 33%.
Based upon the experiments described herein, it is
believed that compositions comprising orange peel extract or
a combination of components of the orange peel extract
including but not limited to tangeretin and nobeletin, may be
included in foods and dietary supplements or "nutraceuticals"
for prevention or treatment of cancer. One of skill can use
the results of experiments in cells and animals described
herein to determine effective amounts to be administered to
other animals, including humans. By "effective amount" it is
meant a concentration that inhibits tumor growth either in
vitro in cells or in vivo in animals. For example, human test
doses can be extrapolated from effective doses in cell
studies, such as ICS0 values, or from effective doses in vivo
by extrapolating on a body weight or surface area basis. Such
extrapolations are routine in the art. C o m p o s i t i o n s
comprising orange peel extracts can be formulated for
administration as a food supplement using one or more fillers.
Alternatively, compositions comprising these extracts can be
administered as conventional pharmaceuticals using one or more
physiologically acceptable carriers or excipients.
Nutraceutical compositions can be formulated for
administration by any route including, but not limited to,
inhalation or insufflation (through mouth or nose), oral,
buccal, parenteral, vaginal, or rectal administration. In one
embodiment, oral administration, the compositions are added
directly to foods and ingested as part of a normal meal.
Various methods are known to those skilled in the art for
addition or incorporation of nutraceuticals into foods.
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Compositions for use in the present invention can also
be administered in the form or tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients
such as binding agents, fillers, lubricants, disintegrants, or
wetting agents. Examples of specific compounds for use in
formulating tablets and capsules are described in detail in
the U.S. Pharmacopeia. Tablets comprising the extract can
also be coated by methods well known in the art. Liquid
preparations for oral administration can also be used. Liquid
preparations can be in the form of solutions, syrups or
suspensions, or a dry product for reconstitution with water or
another suitable vehicle before use. Such liquid preparations
can be prepared by conventional means with pharmaceutically
acceptable additives such as suspending agents, emulsifying
agents, non-aqueous vehicles, and preservatives. Again,
specific additives are well known to those of skill and are
listed in places such as the U.S. Pharmacopeia. In one
embodiment, the oral preparation is formulated to provide
controlled time release of the active nutraceutical
components. For buccal administration the extract can be
formulated as a tablet or lozenge.
For administration by inhalation, compositions for use
in the present invention can be delivered in the form of an
aerosol spray in a pressurized package or as a nebulizer, with
use of suitable propellants. In the case of a pressurized
aerosol, the dosage unit can be determined by providing a
valve to deliver a metered dose.
Parenterally administered compositions are formulated
to allow for injection, either as a bolus or as a continuous
infusion. Formulations for injection can be prepared in unit
dosage forms, such as ampules, or in multi-dose units, with
added preservatives. The compositions for injection can be in
the form of suspensions, solutions, or emulsions, in either
oily or aqueous vehicles. They may also contain formulatory
agents such as suspending agents, stabilizing agents, and/or
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dispersing agents. The active ingredient may also be
presented in powder form for reconstitution with a suitable
vehicle before use. Specific examples of formulating agents
for parenteral injection are found in the U.S. Pharmacopeia.
For rectal administration or vaginal administration,
compositions for use in of the present invention can be
formulated as suppositories, creams, gels, or retention
enemas.
For dietary supplements, the extract can be added in
concentrations up to 5% by weight and mixed according to
methods routine in the art. Dietary supplements for animals
can be prepared in a variety of forms including, but not
limited to, liquid, powder, or solid pill forms. In the
present invention, the orange peel extract can administered
either alone or in combination with other phytochemicals known
to affect tumor cell growth, where combining compounds or
extracts would lead to synergistic effects. Examples of other
phytochemicals which can be used in combination with orange
peel extract include, but are not limited to, resveratrol and
its hydroxylated and methoxylated analogs, rosemary extract,
black tea extracts, Mexican Bamboo, and Huzhang extracts.
Many plants, such as Mexican Bamboo and Huzhang, contain
high amounts of an active component known as resveratrol.
Resveratrol is a well known, biologically active
phytochemical. Resveratrol and its hydroxylated and
methoxylated analogs have been shown to have activity both in
vitro and in vivo to affect cell proliferation and tumor cell
growth. Resveratrol and several of its analogs (3,5-
dihydroxystilbene: R-1; 3, 3', 4, 51-tetrahydroxystilbene: R-
2; 3, 4, 4', 5-tetrahydroxystilbene: R-3; 3, 3', 5, 5'-
tetrahydroxystilbene (R-4), 3, 3', 4, 5, 5'-
pentahydroxystilbene: R-5; 3, 5-dimethoxystilbene: MR-1; 3,
4', 5-trimethoxystilbene: MR-0; 3, 3', 4, 5'-
tetramethoxystilbene: MR-2; 3, 4, 4', 5-tetramethoxystilbene:
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MR-3; 3, 3', 5' 5'-tetramethoxystilbene: MR-4; and 3, 3', 4,
5, 5'-pentamethoxystilbene: MR-5) were evaluated in cell
culture studies using standard methodologies.
W138 human diploid fibroblasts and cancerous SV40-
transformed W138 cells (W138VA) were used in a cell
proliferation assay. Growth rate and viability of these cells
was determined following addition of resveratrol or one of its
analogs. Doses tested ranged from 50 ng to 300 g per ml or
1 M to 100 M concentrations in culture media. Resveratrol
inhibited cell growth at concentrations less than 10 AM. The
resveratrol analogs R3 and MR-0 also inhibited cell growth.
At a concentration of 1 AM, MR-3 completely blocked
proliferation of W138VA cells, although it had no effect on
growth of W138 cells. MR-4 inhibited growth of W138 cells but
not W138VA cells at doses of 100 AM. MR-1 was not active as
an inhibitor of cell growth even at doses as high as 100 AM.
Treatment of W138 and W138VA cells with resveratrol and
its analogs also led to morphological changes in the cells.
Treatment of W138 cells with resveratrol and its analogs R-1
and R-3 led to elongation of normal W138 cells. Methoxy
analogs such as MR-0 and MR-3 caused the flattening of W138
cells. This flattening was accompanied by an increase in
neutral R-galactosidase activity as indicated by an increase
in staining. An increase in activity of (3-galactosidase is
characteristic of senescent cells, indicating that these
analogs modulate the life-span of normal cells.
Resveratrol and its analogs were also tested in
preneoplastic 184-B5/HER human mammary epithelial cells.
Results showed that there was a dose-dependent inhibition of
growth in response to treatment with resveratrol as well as
the methoxy derivatives MR-0, MR-2 and MR-3. The
concentration that inhibited growth by 50% (IC50) for the
tested compounds were: resveratrol, 10.5 AM; MR-0, 10.5 AM;
MR-2 120 AM; MR-3, 1.0 AM. A cell cycle analysis revealed
that treatment with MR-0, MR-2 and MR-3 resulted in
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progressive arrest of cells in the G2/M phase relative to
solvent-treated control cultures and that MR-3 was the most
effective compound.
The in vivo tumor inhibitory effects of MR-3 were tested
in an orthotransplant model. Mice were transplanted with
oncogene-expressing, preneoplastic breast epithelial cells.
Mice were then divided into groups with the control group fed
AIN-76A diet alone. Another group of mice was fed AIN-76A
diet supplemented with MR-3 (400 ppm) After 12 weeks of
continuous feeding, all mice in the control group exhibited
palpable tumor formation at the transplant sites (100% tumor
incidence). In contrast, the group fed diet supplemented with
the analog MR-3 had a 20% tumor incidence, with only one mouse
of the five tested exhibiting tumor growth. Weight gains in
the groups were comparable indicating that the analog had
little toxicity.
This series of studies, both in vitro and in vivo,
indicated that resveratrol as well as analogs of resveratrol
have biological activity related to preventing progression of
cancer in cells.
Extracts of rosemary have also been shown to have anti-
tumor activity and chemopreventive properties (Huang et al.
1994. Cancer Res.54:701-708; Tokuda et al. 1986. Cancer Lett.
33:279-285; Singletary et al. 1996. Cancer Lett. 104:43-48;
Singletary, K.W. and J.M. Nelshoppen. 1991. Cancer Lett.
60:169-175). For example, a diet containing 1% of rosemary
extract significantly inhibited the initiation of mammary
tumorigenesis in rats (Singletary, K.W. and J.M. Nelshoppen.
1991. Cancer Lett. 60:169-175). Palpable tumor incidence in
rats fed the rosemary extract was 47% less than that of rats
fed a control diet. Therefore, rosemary extracts were cancer
preventive.
Black tea and its extracts have also been well-studied
as potential pharmacological agents. Epidemiological studies
have suggested that tea consumption has a protective effect
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against certain forms of human cancer (Stoner, G.D. and H.
Mukhtar. 1995. J. Cell Biochem. Suppl. 22:169-180; Fujiki et
al. 1996. Nutr. Rev. 54:S67-S70). In addition, extracts of
black tea in particular have been shown to be potent
inhibitors of tumorigenesis in several animal model systems
(Javed et al. Biomed. Environ. Sci. 11:307-313; Yang et al.
1997. Carcinogenesis 18:2361-2365; Weisberger et al. 1998.
Carcinogenesis 19:229-232; Rogers et al. 1998. Carcinogenesis
19:1269-1273). Therefore, black tea extracts are known to be
tumor preventive agents.
Accordingly, it is believed that a combination diet of
dietary supplement comprising orange peel extract and at least
one other phytochemical will also be useful to treat or
prevent cancer in animals, including humans. Orange peel
extract may be used in combination with rosemary extract,
resveratrol and its analogs, Mexican Bamboo or Huzhang
extracts, and black tea extracts. Doses of each extract used
in the combination product are selected based on known
activity of the extract in animals or cells.
