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The Role of Zyflamend, an Herbal Anti-inflammatory, as a Potential Chemopreventive Agent Against Prostate Cancer: A Case Report Samuil Rafailov, Sam Cammack, Brian A. Stone and Aaron E. Katz Integr Cancer Ther 2007; 6; 74 DOI: 10.1177/1534735406298843 The online version of this article can be found at: http://ict.sagepub.com/cgi/content/abstract/6/1/74

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Zyflamend as a Potential Chemopreventive Agent Against Prostate Cancer

The Role of Zyflamend, an Herbal Antiinflammatory, as a Potential Chemopreventive Agent Against Prostate Cancer: A Case Report Samuil Rafailov, Sam Cammack, Brian A. Stone, MD, and Aaron E. Katz, MD

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. Keywords: prostate; herbals; precancer; prostate-specific antigen; prostate cancer

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 antiinflammatory drugs and antioxidants with decreased prostate cancer risk.1 PIN is currently discovered in 16% of all men who undergo ultrasound-guided transrectal 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 antiinflammatory 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. DOI: 10.1177/1534735406298843

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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.

Comments Rising evidence makes it hard to ignore the impact of diet on occurrence and progression of prostate SR, SM, BAS, and AEK are at the Department of Urology, Columbia University, New York, New York. Correspondence: Aaron E. Katz, Department of Urology, Columbia University, Herbert Irving Pavilion, 11th Floor, 161 Fort Washington Avenue, New York, NY 10032. E-mail: [email protected]. INTEGRATIVE CANCER THERAPIES 6(1); 2007 pp. 74-76


Zyflamend as a Potential Chemopreventive Agent Against Prostate Cancer

Figure 1 High-grade prostatic intraepithelial neoplasia.

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. INTEGRATIVE CANCER THERAPIES 6(1); 2007

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.6 COX-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


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Rafailov et al clinical trials indicate that COX-2 plays a role in human carcinogenesis and is overexpressed 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 antiinflammatory 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

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double-blind, randomized, placebo-controlled clinical trial. References 1. Nelson WG, De Marzo AM, Deweese TL, Isaacs WB. The role of inflammation in the pathogenesis of prostate cancer. J Urol. 2004;172:S6-S11. 2. Girasole CR, Cookson MS, Putzi MJ, et al. Significance of atypical and suspicious small acinar proliferations, and high grade prostatic intraepithelial neoplasia on prostate biopsy: implications for cancer detection and biopsy strategy. J Urol. 2006;175(3 pt 1):929-933. 3. Shepherd D, Keetch DW, Humphrey PA, et al. Repeat biopsy strategy in men with isolated prostatic intraepithelial neoplasia on prostate needle biopsy. J Urol. 1996;156:460-463. 4. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol. 2006;175: 820-834. 5. Weinstein MH, Epstein JI. Significance of high-grade prostatic intraepithelial neoplasia on needle biopsy. Hum Pathol. 1993;24:624. 6. Bemis DL, Capodice JL, Anastasiadis AG, Katz AE, Buttyan R. Zyflamend®, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. Int J Nutr Cancer. 2005; 52:202. 7. Akaza H, Miyanaga N, Takashima N, et al. Comparisons of percent equal producers between prostate cancer patients and controls: case controlled studies of isoflavones in Japanese, Korean and American residents. Jpn J Clin Oncol. 2004;34:86-89. 8. Landis SH, Murry T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin. 1998;48:6-29. 9. Morton MS, Griffiths K, Blacklock N. The preventive role of diet in prostatic disease. Br J Urol. 1996;77:481-483. 10. Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC. A prospective study of tomato products, lycopene, and prostate cancer risk. J Natl Cancer Inst. 2002;94:391-398. 11. Trichopoulou A, Lagiou P, Kuper H, Trichopoulos D. Cancer and Mediterranean dietary traditions. Cancer Epidemiol Biomarkers Prev. 2000;9:537-543. 12. Shahedi K, Lindström S, Zheng SL, et al. Genetic variation in the COX-2 gene and the association with prostate cancer risk. Int J Cancer. 2006;119:668-672.

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CANCER THERAPIES 6(1); 2007