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Memorial Sloan-Kettering Cancer Center, New York, NY 10021 and Weill Medical College of Cornell University, New York, NY 10021
3To whom correspondence should be addressed. E-mail: pintoj{at}mskcc.org
ABSTRACT
There is increasing evidence that allium derivatives from garlic have significant antiproliferative actions on human cancers. Both hormone-responsive and hormone-unresponsive cells lines respond to these derivatives. The effects shown by allium derivatives include induction of apoptosis, regulation of cell cycle progression and modification of pathways of signal transduction. Allium derivatives appear to regulate nuclear factors involved in immune function and inflammation, as well as in cellular proliferation. Our own studies indicate that allium derivatives inhibit proliferation of the human prostate cancer cell line (LNCaP) and the human breast cancer cell line (MCF-7). Further research is required to clarify the mechanisms of inhibition of cellular proliferation by allium derivatives and to explore their potential application to cancer prevention and control.
KEY WORDS: • garlic • allium • human prostate cancer • LNCaP cells • human breast cancer • MCF-7 cells
In examining the inhibition of cancer growth in model systems, a number
of studies show potent anticancer action of allium derivatives in model
tumor systems. For example, a variety of allysulfides inhibit
gastrointestinal tract malignancies induced by the carcinogens,
1,2-dimethylhydrazine (Sumiyoshi and Wargovich 1990
),
benzo(a)pyrene (Hu et al. 1997
, Sparnins et al. 1988
) and N-nitroso compounds
(Wattenberg et al. 1989
).
One of the possible mechanisms of action of allium derivatives may be
to inhibit the enzyme cytochrome P450 2E1. This
enzyme activates a number of xenobiotic substances, including
carcinogens such as nitrosamines, hydrazines and halogenated
hydrocarbons (Brady et al. 1991
).
By inhibiting the activation of carcinogens, the allium derivatives may
potentially render these agents less capable of initiating the
carcinogenic process. One likely event in this process may involve
inhibiting the formation of DNA adducts with carcinogens. Allium
constituents have been shown to inhibit the covalent binding of the
carcinogen, 7,12-dimethylbenz[a]anthracene, to DNA, an intracellular
event that correlates with decreased mutagenesis and carcinogenesis
(Milner 1996
). The effect of allylsulfides on
P450 enzymes appears to be specific rather than
general in that the activities of other demethylating and hydroxylating
cytochromes, namely, P450 2B1, 1A1 and 1A2, are
actually elevated by allium components (Pan et al. 1993
,
Siess et al. 1997
).
Metabolism of steroid hormones occurs through the same cytochrome
P450 enzymes induced by allylsulfide derivatives,
namely, P450 1A1 and 1A2. Consumption of garlic
and garlic-derived compounds has been shown to alter the rate of
metabolism of estrogen and testosterone through regulation of one or
more of the cytochrome P450 enzymes
(Sepkovic et al. 1996
, Siess et al. 1997
). This effect is likely to be a critical mechanism whereby
dietary constituents such as garlic can exert specific action in
inhibiting the development of hormone-sensitive cancers.
In addition to modifying the metabolism of drugs, hormones and
xenobiotic substances (Phase I metabolism) by regulating a number of
cytochrome P450 enzymes, allium derivatives can
selectively induce Phase II conjugation systems, which inactivate most
carcinogens (Hu et al. 1997
, Sparnins et al. 1982
). Glutathione S-transferase
(GST),4
a multigene family of conjugating enzymes, and glucuronyltransferase
protect cells directly against the effects of carcinogens and a variety
of xenobiotic compounds. Allium constituents, such as diallyldisulfide
or allylmethyltrisulfide, induce formation of these Phase II enzymes,
perhaps providing protection against cancer growth in model systems
induced by carcinogenic and mutagenic agents.
Another effect of allium compounds that possibly relates to inhibition
of carcinogenesis is stimulation of glutathione (GSH) synthesis. This
compound detoxifies carcinogens, serves as an intracellular antioxidant
(protecting cell membranes and intracellular components from damage by
free radicals) and assists in the regulation of DNA synthesis.
GSH not only functions as a cosubstrate for the family of GST, enzymes
necessary for conjugating GSH to electrophiles and thus blocking
DNA-adduct formation, but also serves as a reductant for
glutathione peroxidase (Perchellet et al. 1986
). This
selenoenzyme protects cells against lipid peroxidation by using GSH to
reduce organic peroxides to nonreactive hydroxy fatty acids and
alcohols with concomitant formation of oxidized glutathione (GSSG).
Allysulfides enhance glutathione peroxidase activity (Meister and Anderson 1983
, Perchellet et al. 1986
) and
affect sulfhdryl/disulfide exchange reactions that may be critical for
the control of proliferation and cell cycle regulation (Ziegler 1985
). Treatment of isolated epidermal cells with a single
exposure of diallylsulfide results in a sustained
concentration-dependent increase in glutathione peroxidase activity
(Perchellet et al. 1986
). Moreover, these cells
demonstrate a marked increase in the intracellular ratio of GSH to
GSSG, indicating either enhanced de novo formation or diminished
utilization of GSH, likely due to the presence of other antioxidant
components in garlic extracts.
Thus, garlic-derived allylsulfides may exert their anticarcinogenic effects in experimental animals and in cell culture systems by blocking P450 enzymes included in carcinogen activation and/or by enhancing P450 enzymes that catabolize carcinogens to less reactive intermediates. This latter effect, when it occurs in hormone-sensitive cancers, such as breast and prostate, may diminish responsiveness of these tissues to the steroid hormones, estrogen or testosterone, respectively. Allylsulfides stimulate synthesis of GSH, which detoxifies carcinogens and other xenobiotics, serves as an intracellular antioxidant and regulates DNA synthesis.
Effects of allium derivatives on tumor proliferation and promotion.
Evidence is accumulating that allium derivatives from garlic hold
considerable promise in inhibiting proliferation and promotion of a
variety of tumors in both experimental animals and humans. In addition
to the potential use of allium compounds in cancer prevention and in
blocking the initiation phases of chemical carcinogenesis, studies have
demonstrated that garlic constituents inhibit growth of transplantable
tumors and have antipromotional activity against a number of
hormone-sensitive and hormone-refractory tumor cell lines
(Takeyama et al. 1993
).
For example, S180 tumor cells exposed to a garlic extract exhibit
delayed progression of S phase and accumulation in G1 (Lee et al. 1994
). These studies of cell cycle progression suggest that
allylsulfide derivatives can block signal transduction pathways that
lead to expression of nuclear transcription factors, an interaction
that is demonstrable in lymphocytes subjected to oxidative stress.
S-Allylcysteine treatment of human T lymphocytes blocks the
activation of nuclear factor 
B (NF-B), a member of the Rel
oncogene family that regulates gene encoding for proteins associated
with immune function, inflammation and cell proliferation (Geng et al. 1997
). In a similar fashion, ajoene, a lipid-soluble
component of garlic, influences formation of NF-B and induces
apoptosis in human promyeloleukemic cells (Dirsch et al. 1998
). The evidence to date suggests that allium derivatives
can block pathways that lead to expression of nuclear transcription
factors, proteins that regulate the progression of cancer cells through
their growth cycles.
Other studies show that allium derivatives suppress the growth of
oncogene-transformed tumors in mice (Singh et al. 1996
). Studies on the ras family of protooncogenes
have shown that diallyldisulfide suppresses the growth of
H-ras oncogene-transformed tumors in nude mice by
blunting the association of a mutated p21H-ras protein with
the cell membrane compartment, an interaction that is associated with
transformation of some premalignant cells (Singh et al. 1996
).
These studies, taken as a whole, indicate that allium constituents from garlic may affect cancer cells by regulating factors that control cell cycle progression. The possible targets of these derivatives may include, among others, alterations in metabolism of steroid hormones (as described in the section on P450-induced modification) and the regulation of cell cycle transcription factors, perhaps mediated by changes in oxidation-reduction balance.
In summary, allium derivatives have been shown to exert antiproliferative activity on normal and malignant cells and possibly to block progression of tumor cells to more aggressive phenotypes.
Effects of allium derivatives on model systems for human prostate and breast cancer cells.
A useful model system for the study of prostate cancer is the LNCaP cell line of human prostate cancer cells. This cell line retains many of the features of clinical prostate cancer, such as responsiveness to testosterone and production of the well-known prostate biomarkers, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP).
In a recent report from our institution (Wang et al. 1995
), the rate of growth of LNCaP tumors implanted into nude
mice was markedly retarded by a low fat diet and greatly accelerated by
feeding mice a typical high fat, Western-style diet. Using these
cells, our research group has shown that allium derivatives from garlic
have a strong antiproliferative effect (Pinto et al. 1997a
), as illustrated in Figure 1
.
|
), growth inhibition by the
garlic constituent, S-allylmercaptocysteine (SAMC), was
accompanied by a reduction in secretion of PSA. The reduction in
secretion of this biomarker was even greater than the reduction in the
rate of cell growth. In contrast to its effect on PSA secretion, SAMC
increased expression and activity of a newly identified marker for
prostate cancer progression called prostate-specific membrane
antigen (PSMA). We have identified PSMA as a unique transmembraneous
folate hydrolase with exopeptidase activity that cleaves 
-glutamyl
linkages from polygammaglutamated folates with accumulation of folate
(Pinto et al. 1996
). Unlike the reduction in PSA
expression in LNCaP that results from testosterone deprivation,
PSMA-folate hydrolase expression increases under these
conditions. Other recent studies have shown that SAMC provokes a twofold increase in the rate of removal of testosterone from the LNCaP cells grown in culture. Thus, specific garlic constituents may alter the levels of recognized biomarkers of prostate cancer, perhaps in part by enhancing the rate of testosterone degradation. We hypothesize that allium derivatives affect induction of selective P450 enzymes, resulting in changes in the rate of testosterone degradation. We propose further that the metabolites formed are largely inactive and may not evoke responses in prostate cancer cells that express mutated androgen receptors, such as LNCaP cells. These findings in their entirety suggest that allium derivatives may act, at least in part, by enhancing the rate of catabolism of testosterone.
Other useful model systems in which anticancer effects of garlic
derivatives have been shown are the human breast cancer cell lines,
MCF-7 and MCF-7ras, which retain many features of
human breast cancer clinically. In cell culture, garlic extracts
significantly inhibit anchorage-independent growth of these cells
(Li et al. 1995
) as shown in Table 1
.
|
FOOTNOTES
1 Presented at the conference "Recent Advances
on the Nutritional Benefits Accompanying the Use of Garlic as a
Supplement" held November 15–17, 1998 in Newport Beach, CA. The
conference was supported by educational grants from Pennsylvania State
University, Wakunaga of America, Ltd. and the National Cancer
Institute. The proceedings of this conference are published as a
supplement to The Journal of Nutrition. Guest editors:
John Milner, The Pennsylvania State University, University Park, PA and
Richard Rivlin, Weill Medical College of Cornell University and
Memorial Sloan-Kettering Cancer Center, New York, NY. 
2 Supported in part by the Clinical Nutrition
Research Unit grant (CA-29502) from the National Institutes of Health.
Partial funding was also provided by grants from Wakunaga of America,
the Frank J. Scallon Medical Research Foundation, The Ronald and Susan
Lynch Foundation, the Sunny and Abe Rosenberg Foundation, The Rosenfeld
Heart Foundation, Now Natural Foods and the Allen Foundation. Portions
of the research on prostate cancer were performed in coordination with
the Nutrition Research Laboratory and the George M. O’Brien Urology
Research Center, Memorial Sloan-Kettering Cancer Center.
4 Abbreviations used: GSH, glutathione; GSSG,
oxidized glutathione; GST, glutathione S-transferase;
NF-B, nuclear factor B; PAP, prostatic acid phosphatase; PSA,
prostate-specific antigen; PSMA, prostate-specific membrane
antigen; SAMC, S-allylmercaptocysteine.
REFERENCES
1. Brady J. F., Ishizaki H., Fukuto J. M., Lin M. C., Fadel A., Gapac J. M., Yang C. S. Inhibition of cytochrome P450 IIE1 by diallyl sulfide and its metabolites. Chem. Res. Toxicol. 1991;4:642-647[Medline]
2.
Dirsch V. M., Gerbes A. L., Vollmar A. M. Ajoene, a compound of garlic, induces apoptosis in human promyeloleukemic cells, accompanied by generation of reactive oxygen species and activation of nuclear factor B. Molec. Pharmacol. 1998;53:402-407
3. Geng Z., Rong Y., Lau B. H. S. S allyl cysteine inhibits activation of nuclear factor kappa B in human T cells. Free Radical Biology Med 1997;23:345-350
4. Hu X., Singh S. V. Glutathione S-transferases of female A/J mouse lung and their induction by anticarcinogenic organosulfides from garlic. Arch. Biochem. Biophys. 1997;340:279-286[Medline]
5. Lee E. S., Steiner M., Lin R. Thioallyl compounds: Potent inhibitors of cell proliferation. Biochim. Biophys. Acta. 1994;1221:73-77[Medline]
6. Li G., Qiao C. H., Lin R. I., Pinto J. T., Osborne M. P., Tiwari R. K. Antiproliferative effects of garlic constituents on cultured human breast cancer cells. Oncol. Rep. 1995;2:787-791
7. Meister A., Anderson M. E. Glutathione. Annu. Rev. Biochem. 1983;52:711-760[Medline]
8. Milner J. A. Garlic: its anticarcinogenic and antitumorigenic properties. Nutr. Rev. 1996;54:S82-S86[Medline]
9. Pan J., Hong J. Y., Ma B. L., Ning S. M., Paranawithana S. R., Yang C. S. Transcriptional activation of P-450 2B1/2 genes in rat liver by diallyl sulfone, a compound derived from garlic. Arch. Biochem. Biophys. 1993;302:337-342[Medline]
10. Perchellet J. P., Perchellet E. M., Abney N. L., Zirnstein J. A., Belman S. Effects of garlic and onion oils on glutathione peroxidase activity, the ratio of reduced and oxidized glutathione and ornithine decarboxylase induction in isolated mouse epidermal cells treated with tumor promoters. Cancer Biochem. Biophys. 1986;8:299-312[Medline]
11.
Pinto J. T., Qiao C. H., Xing J., Rivlin R. S., Protomastro M. L., Weissler M. L., Tao Y., Thaler H., Heston W.D.W. Effects of garlic thioallyl derivatives on growth, glutathione concentration, and polyamine formation of human prostate carcinoma cells in culture. Am. J. Clin. Nutr. 1997a;66:398-405
12. Pinto J. T., Qiao C. H., Xing J., Brian P., Suffoletto B. P., Schubert K. B., Rivlin R. S., Huryk R. F., Bacich D. J., Heston W. D. W. Alterations of prostate biomarker expression and testosterone utilization in human LNCaP prostatic carcinoma cells by garlic-derived S-allylmercaptocysteine. The Prostate 2000;45:304-314[Medline]
13. Pinto J. T., Suffoletto B. P., Berzin T. M., Qiao C. H., Lin S., Tong W. P., May F., Mukherjee B., Heston W. D. W. Prostate specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. Clinical Cancer Res 1996;2:1445-1451[Abstract]
14. Sepkovic D. W., Qiao C., Pinto J. T., Bradlow H. L. Phase II metabolism of various estrogens after treatment with aged garlic extract 1996 American Association for Cancer Research Washington, DC.
15. Siess M. H., Le Bon A. M., Canivenc-Lavier M. C., Suschetet M. Modification of hepatic drug-metabolizing enzymes in rats treated with alkyl sulfides. Cancer Lett 1997;120:195-201[Medline]
16. Singh S. V., Mohan R. R., Agarwal R., Benson P. J., Hu X., Rudy M. A., Xia H., Katoh A., Srivastava S. D., Mukhtar H., Gupta V., Zaren H. A. Novel anti-carcinogenic activity of an organosulfide from garlic: inhibition of H-ras oncogene transformed tumor growth in vivo by diallyldisulfide is associated with inhibition of p21H-ras processing. Biochem. Biophys. Res. Commun. 1996;225:660-665[Medline]
17.
Sparnins V. L., Barany G., Wattenberg L. W. Effects of organosulfur compounds from garlic and onion on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse. Carcinogenesis 1988;9:131-134
18. Sparnins V. L., Venegas P. L., Wattenberg L. E. Glutathione S-transferase activity: enhancement by compounds inhibiting chemical carcinogenesis and by dietary constituents. J. Natl. Cancer Inst. 1982;68:493-496
19.
Sumiyoshi H., Wargovich M. J. Chemoprevention of 1,2-dimethylhydrazine-induced colon cancer in mice by naturally occurring organosulfur compounds. Cancer Res 1990;50:5084-5087
20. Takeyama H., Hoon D.S.B., Saxton R. E., Morton D. L., Irie R. F. Growth inhibition and modulation of cell markers of melanoma by S-allylcysteine. Oncology 1993;50:63-69[Medline]
21.
Wang Y., Corr J. G., Thaler H. T., Tao Y., Fair W. R., Heston W.D.W. Decreased growth of established human prostate LNCaP tumors in nude mice fed a low-fat diet. J. Natl. Cancer Inst. 1995;87:1456-1462
22.
Wattenberg L. W., Sparnins V. L., Barany G. Inhibition of N-nitrosodiethylamine carcinogenesis in mice by naturally occurring organosulfur compounds and monoterpenes. Cancer Res 1989;49:2689-2692
23. Ziegler D. M. Role of reversible oxidation-reduction of enzyme thiols-disulfides in metabolic regulation. Annu. Rev. Biochem. 1985;54:305-329[Medline]
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