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Correlation between dietary intake and occurrence of
prostate cancer has gained significant support in recent years.
Although a direct correlation has yet to be proven between
inflammation and prostate cancer, chronic or recurrent inflammation
has been hypothesized to be the major predisposing factor for this
disease. The authors have been studying
Zyflamend, a novel herbal anti-inflammatory mixture, as a
potential chemopreventive agent in a phase 1 trial for patients
diagnosed with prostatic intraepithelial neoplasia. They report the
results of the first patient who has completed the 18-month study in
which 24 patients were assigned to a cohort and placed on successive
herbal supplement regimen starting with
Zyflamend alone. Click Here for
Zyflamend product information.
Prostatic intraepithelial neoplasia (PIN) is
strongly believed to be a precursor of prostate cancer. The role of
inflammation and prostate cancer development has been widely
studied, and data have correlated prostatitis and sexually
transmitted infections with increased prostate cancer risk and
intake of anti- inflammatory drugs and antioxidants with decreased
prostate cancer risk.1 PIN is currently discovered in 16% of all men
who undergo ultrasound-guided trans- rectal needle biopsy of the
prostate. Of these 16% diagnosed, 22% to 24% will develop prostate
cancer in the future.2-5 Our laboratory has demonstrated that
Zyflamend can have an effect on
prostate cancer cell growth and interfere with cell cycle pathways.6
Although the compound has demonstrated cyclooxygenase (COX)-2
activity, the mechanism of action may be COX independent.
We discuss the effect of
Zyflamend, an herbal anti- inflammatory formulation composed of
extracts of rosemary, turmeric, ginger, holy basil, green tea, hu
zhang, Chinese goldthread barberry, oregano, and
Baikal skullcap, on its ability
to prevent prostate cancer in a patient with high-grade PIN (HGPIN)
by COX-inhibiting activity.
Case Report
A 70-year-old African American man with no
significant past medical history presented with an elevated
prostate-specific antigen (PSA) level of 9.7 ng/mL. He underwent a
12-core biopsy in May 2004. The biopsy revealed HGPIN in 1 of 12
cores (Figure 1). The patient was informed of a phase 1
institutional review board–approved clinical trial being conducted
at Columbia University Medical Center using an herbal
anti-inflammatory compound known as Zyflamend (New Chapter Inc,
Brattleboro, VT). The patient agreed to enroll in the study. The
study required that patients take Zyflamend orally 3 times a day
with each meal and return to the clinic every 3 months for routine
blood tests. At the 6-, 12-, and 18-month visits of the study, the
patient underwent subsequent 12-core prostate biopsy. In addition,
at baseline and the 6-, 12-, and 18-month visits, the patient had an
electrocardiogram.
Based on the number of consumed capsules, the
patient was 93% compliant (80% was set as the minimum acceptable
compliance rate for this trial). Throughout the study, the patient’s
mean PSA level was 8.93 ng/mL (range, 8.0-10.2 ng/mL; Figure 2). Of
the 3 biopsies, the 6-month biopsy revealed benign prostatic
hyperplasia alone. The 12-month biopsy showed PIN in 1 of 12 cores,
and the final 18-month biopsy was again negative for cancer and PIN.
At the end of this 18-month trial in March 2006, the patient was
cancer and HGPIN free (Figure 3). COX-2 stains were also found to be
negative (Figures 4 and 5). Laboratory tests of the blood samples
withdrawn during the visits did not reveal any clinically
significant changes.
Figure 1 High-grade prostatic intraepithelial neoplasia.
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Figure 2 Prostate-specific antigen for the period of the trial. |
Figure 3 Normal prostatic tissue at the end of the clinical
trial. |
Figure 4 Weakly positive staining for cyclooxygenase-2 after 2
of the 3 trials had been completed. |
Figure 5 Negative staining for cyclooxygenase-2 at the end of
the trial. |
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Comments
Rising evidence makes it hard to ignore the impact
of diet on occurrence and progression of prostate cancer. Dissimilar
rates of prostate cancer occurrence rate and mortality observed
between Eastern and Western cultures,7-9 and even more juxtaposed
geographic areas such as the Mediterranean and Eastern Europe,10,11
are striking.
Arachidonic acid, and its precursor, linoleic
acid, are present in significant quantities in animal fats and a
variety of vegetable oils. The elevated intake of these fatty acids
increases the substrate concentration for COXs, enzymes responsible
for converting arachidonic acid into potent signaling molecules
called prostaglandins.6COX-2, 1 of 2 COX enzymes, is a key enzyme in
the conversion of arachidonic acid to prostaglandin. The
prostaglandins produced by COX2 are involved in inflammation and
pain response in different tissues in the body, including the
prostate. Accumulating evidence from epidemiologic studies, chemical
carcinogen-induced rodent models, and clinical trials indicate that
COX-2 plays a role in human carcinogenesis and is over expressed in
prostate cancer tissue.12
In the laboratory, we considered the potential
COX-inhibitory activity of Zyflamend
and analyzed its effects on the human prostate cancer cell line
LNCaP. COX inhibitory activity of
Zyflamend was determined by a spectrophotometric-based assay
using purified ovine COX-1 and COX-2 enzymes. We also observed
decreased COX-2 levels in the patient who completed the clinical
trial. Effects of Zyflamend on LNCaP cell growth and apoptosis in
vitro were assessed by cell counting, Western blot detection of poly
ADP-ribose polymerase cleavage, and measurement of caspase-3
activity in treated and control cell extracts.6
HGPIN refers to architecturally benign prostatic
acini and ducts lined by atypical cells. These atypical cells share
morphological, histochemical, immunohistochemical, and genetic
changes with cancer but lack invasion of the basement membrane of
the prostatic gland.4 Because of these similarities, HGPIN and
inflammation are believed to lead to development of prostate cancer.
In this phase 1 trial of
Zyflamend, an herbal anti-inflammatory mixture, a patient
diagnosed with HGPIN was PIN- and cancer-free. However,
Zyflamend did not appear to affect the
PSA level, but it is also possible that it prevented PSA increase
(Figure 2). The absence of HGPIN upon the biopsy may have been a
result of a sampling error. Because of a small amount (1 of 12
cores) of HGPIN discovered upon the initial biopsy, it is possible
that HGPIN is finely confined to the region that was missed in the
biopsy. Results attained from the remaining patients in the trial
will help to determine if this complex herbal mixture warrants
further assessment as a prostate cancer chemopreventive agent in a
double-blind, randomized, placebo-controlled clinical trial.
References
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