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Department of Microbiology and Immunology and Department of Medicine, Division of Oncology, New York Medical College, Valhalla, NY 10595
3To whom correspondence should be addressed. E-mail: jan_geliebter{at}nymc.edu
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INTRODUCTION |
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 TOP INTRODUCTION REFERENCES |
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32,000 deaths
will be attributed to the disease (Greenlee et al. 2000
). Prostate cancer is the most common malignancy of men in
the United States and the second leading cause of cancer deaths
(Greenlee et al. 2000
). Because there is no cure for
metastatic prostate cancer, research directed toward the development of
new treatments for metastatic disease is imperative. The
chemopreventive and therapeutic potential of phytochemicals is now the
subject of intense research, and the molecular mechanisms of their
actions are being reported (Adlercreutz 1995
,
Jang et al. 1997
, Knight and Eden 1996
,
Kohlmeier et al. 1995
). For example, genistein has been
shown to be a protein tyrosine kinase inhibitor as well as an inhibitor
of DNA topoisomerase II and angiogenesis (Fotsis et al. 1995
, Peterson 1995
, Planchon et al. 1995
, Spinozzi et al. 1994
, Traganos et al. 1992
). Coumestrol is thought to be an inhibitor of 17
ß-hydroxysteroid oxidoreductase type 1, the enzyme that converts
estrone to 17ß-estradiol (Makela et al. 1995
). We have
shown that the chemopreventive compound indole-3-carbinol, a
phytoestrogen, acts by interfering with the signal transduction pathway
of the estrogen receptor in breast cancer cells (Tiwari et al. 1994
). The phytoestrogens dl-aminoglutethimide and
apigenin can inhibit the enzyme aromatase, which converts testosterone
to estradiol and androstenedione to estrone (Pelissero et al. 1996
). Thus, several phytochemicals appear to disrupt specific
biochemical functions crucial to sex hormone metabolism and cell cycle
control. Intense interest has focused on these properties of
phytochemicals as an alternative therapeutic approach for
hormone-refractory prostate cancer.
PC-SPES is a refined herbal powder sold as an over-the-counter food
supplement (Botanic Labs, Brea, CA). It is made from Ganoderma
lucidium Karst, Dendranthema morifolium Tzvel,
Glycyrrhiza glabra L., Isatis indigotica Fort,
Panax pseudoginseng Wall, Rabdosia rubescens,
Scutellaria baicalensis Georgi and Serenoa repens.
Clinical reports have indicated that dietary supplementation with
PC-SPES by prostate cancer patients results in a dramatic decrease
in their prostate-specific antigen (PSA) levels (de la Talle et al. 2000
, DiPaola et al. 1998
, Moyad et al. 1999
). At least part of the dramatic effect of
PC-SPES on PSA levels in patients may be attributable to the
estrogenic activity of the mixture. Gynecomastia and loss of libido
have been reported to be side effects of high dose PC-SPES
consumption, but these side effects appear not to occur at lower doses
of the herbal mixture (de la Talle et al. 2000
,
DiPaola et al. 1998
, Moyad et al. 1999
).
The estrogenic activity of PC-SPES has also been demonstrated
experimentally with yeast transcription activation assays and uterine
weight assays in mice (DiPaola et al. 1998
).
Cell culture studies by several groups have indicated that PC-SPES
induces profound biochemical changes in prostate cancer cells.
Halicka et al. (1997)
found that an ethanol extract of
PC-SPES decreases the clonogenicity of the human prostate cancer
cell lines PC-3 and LNCaP, and alters the cell cycle distribution of
PC-3 cells. They found that PC-SPES also affected several other
cancer cell lines, including the breast cancer cell line MCF-7, the
melanoma cell line Colo 38 and the histocytic line U937. Hsieh et al. (1997)
demonstrated that an ethanol extract of
PC-SPES down-regulated proliferating cell nuclear antigen, and
androgen receptor expression and PSA secretion in LNCaP cells.
Kubota et al. (2000)
found that an ethanol extract of
PC-SPES inhibited clonal growth of the prostate cancer lines LnCaP,
PC-3 and DU145, and altered the cell cycle distribution in these cells.
Similarly, de la Taille et al. (2000)
found that an
ethanol extract of PC-SPES was effective in inhibiting the growth
of LNCaP, PC-3 and DU145 cells.
We used a well-established rat model of prostate cancer—the highly aggressive, hormone-refractory rat prostate cancer cell line, MAT-LyLu. This prostate cancer cell line is one of several variant cell lines isolated from a heterogeneous prostate cancer lesion in a Copenhagen rat. When injected into Copenhagen rats, it forms a rapidly growing tumor and quickly metastasizes to lymph nodes and lung. MAT-LyLu cells grow rapidly, are negative for androgen and estrogen receptors and grow equally well in normal and castrated Copenhagen rats. Thus, the MAT-LyLu/Copenhagen rat is a model for hormone-independent, metastatic prostate cancer.
We have demonstrated that incorporating PC-SPES into the Copenhagen
rat diet significantly protects rats from transplantable MAT-LyLu
tumor cells (Tiwari et al. 1999
). This is noteworthy
because the MAT-LyLu cell line is nonimmunogenic and highly
resistant to treatment. In two experiments involving a total of 26
Copenhagan rats, experimental rats were acclimatized to Purina 5001
Rodent Chow formulated with 0.05% PC-SPES, whereas control
rats were fed standard 5001 Chow. Rats were then challenged with an
intradermal injection of 10,000 MAT-LyLu cells. Six of 13 rats fed
the PC-SPES–supplemented diet were protected against tumor challenge,
whereas all control rats developed tumors (P < 0.002)
(Fig. 1
).
|
To assess whether ethanol extracts or water extracts of PC-SPES
contain antiprostate cancer cell activity in vitro, 5 x 104 Mat-LyLu cells were grown for 3 d in
100-mm tissue culture plates in RPMI medium containing 0.2% ethanol or
water extracts of PC-SPES. Controls consisted of medium alone or
medium with vehicle (0.2% ethanol). Triplicate cultures were harvested
by trypsinization and viable cells (trypan blue exclusion) were
counted. Ethanol extracts (P < 0.0042) and water
extracts (P < 0.0009) both significantly inhibited
MAT-LyLu cell growth, with water extracts of PC-SPES being
slightly more inhibitory (Fig. 2
).
|
, Kubota et al. 2000
). It has also been
suggested that PC-SPES mediates its effect by potentiating the
immune response (Hsieh et al. 1998
). The finding that
PC-SPES is effective in tissue culture systems and in
immunodeficient mice suggests that immunopotentiation is not the only
mode of action of PC-SPES (de la Talle et al. 2000
,
Halicka et al. 1997
, Hsieh et al. 1997
,
Kubota et al. 2000
). Several components of PC-SPES
have been demonstrated to exert significant biological effects.
Ganoderma lucidium Karst exerts strong immunostimulatory
effects in rodents and in vitro (Murasugi et al. 1991
).
An immunomodulatory protein, LZ-8, has been identified as a T-cell
stimulator and its genomic sequence has been cloned (Murasugi et al. 1991
). Baicalein, a flavonoid derived from
Scutellaria baicalensis, has been shown to have
antiproliferative and lipooxygenase-inhibitory activity
(Huang et al. 1994
). Other flavones from S.
baicalensis have been shown to inhibit mouse skin tumor promotion
in two-stage carcinogenesis testing (Konoshima et al. 1992
). Serenoa repens is a potent phytoestrogen, and
an n-hexane lipid/sterol extract of S. repens has
been shown to be an inhibitor of both type 1 and type 2 5
-reductase,
the enzyme that converts testosterone to dihydrotestosterone, the
active androgen in the prostate (Iehle et al. 1995
).
Rg1, a saponin derived from Panax ginseng, has been shown to
stimulate lymphocytes (Liu et al. 1995
). Similarly, a
hot water extract of P. ginseng is mitogenic toward T cells,
both in vivo and in vitro, and the in vitro activity is comparable to
that of Concanavalin A (Mizuno et al. 1994
). Of
particular relevance to the development of metastases, ginsenoside-Rb2
inhibits angiogenesis in B16 melanoma cells in vivo (Sato et al. 1994
). Extracts of Glycyrrhiza glabra have shown
antimutagenic activity in the Salmonella reversion assay
(Shankel and Clarke 1990
, Zani et al. 1993
). The progression of prostate cancer from a localized,
quiescent disease to a clinically relevant and eventually metastatic
cancer has been proposed to involve a series of mutagenic events
(Rinker-Schaeffer et al. 1994
). The antimutagenic
activity of G. glabra may be a significant factor in slowing
or stopping the cascade of prostate cancer progression. Thus, together, the components of PC-SPES are theoretically capable of acting on multiple targets to induce cytostatic and cytotoxic effects on cancer cells. It is perhaps this synergistic interaction and combined effect that may be unique to PC-SPES and may be critical for the observed decrease in PSA levels in prostate cancer patients and its ability to inhibit prostate cancer cell growth, both in vivo and in vitro. In fact, the combined attack on several of the aberrantly expressed metabolic and homeostatic pathways of cancerous cells may be the only way to treat cancer effectively.
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FOOTNOTES |
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2 Funded by the Zalmen A. Arlin Cancer Research Fund and the Zita Spiss Foundation.
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REFERENCES |
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