Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)—Health Professional Version - National Cancer Institute 9/10

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)—Health Professional Version - National Cancer Institute

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version

Multicomponent Therapies

In This Section

• Pomi-T (Pomegranate, Green Tea, Broccoli, and Turmeric)
• Lycopene, Selenium, and Green Tea
• Lycopene and Other Components
• Zyflamend
  • Overview
  • General information and history
  • Preclinical/animal studies
  • Human studies
  • Adverse effects

Pomi-T (Pomegranate, Green Tea, Broccoli, and Turmeric)

In a placebo-controlled, double-blind, randomized study, 199 men with localized prostate cancer were randomly assigned to either a food supplement, Pomi-T, or placebo (2:1) for 6 months.[1] Pomi-T contained 100 mg each of pomegranate whole fruit powder, broccoli powder, and turmeric powder; and 20 mg of green tea extract (equivalent to 100 mg of tea). The herbal ingredients in this supplement were raw, dry, powdered plant materials and one plant extract, none of which were chemically standardized. Chemical standardization is widely performed with herbal extracts, as a means of enhancing the reproducibility of studies with herbal dietary supplements via qualitative and quantitative chemical analysis. There were no significant differences in age or Gleason score between the groups. Forty percent of the patients had rising prostate-specific antigen (PSA) levels following local therapy and 60% were on active surveillance (prelocal therapy). The study found a median rise in PSA of 14.7% after 6 months in the Pomi-T group compared with a 78.5% median rise in PSA in the placebo group. The supplement was well tolerated with no significant increase in adverse events compared with placebo, although a trend was noted towards increased flatulence and loose bowels in the supplement group.

Important differences exist between pomegranate preparation and standardization. While dried fruit powder is commonly found in the marketplace, an equal amount of pomegranate fruit extract has a much higher content of polyphenols that are considered the bioactive constituents and can be used for the chemical standardization of preparations.

Lycopene, Selenium, and Green Tea

In a randomized, double-blinded, placebo-controlled study of a supplement containing lycopene (35 mg), selenium (55 µg), and green tea catechins (600 mg) that was given for 6 months and targeted men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation, a higher incidence of prostate cancer was seen on rebiopsy in men who received the supplement. Although the expected (or historical) rate of progression to prostate cancer is less than 20% (even at 1 year), more than 25.5% of this population of men had a diagnosis of prostate cancer at 6 months, which may be attributed to inadequate sampling and potentially missed cancers at baseline. A high percentage of positive biopsies raises the concern for cancers missed on baseline biopsy, and thus, further study is warranted.[2]

Lycopene and Other Components

One study randomly assigned 79 men before prostatectomy to a nutritional interventionwith tomato products containing 30 mg of lycopene daily; tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea; or a control diet for 3 weeks.[3] There were no differences in PSA values between the intervention and control groups. However, a post hoc exploratory analysis found lower PSA values in men with intermediate-risk prostate cancer who consumed the tomato products and in men with the highest increases in lycopene levels.

Zyflamend

Overview

• Zyflamend is a dietary supplement that contains supercritical fluid (CO2) and hydroalcoholic extracts of the following herbs, combined and suspended in olive oil: rosemary, turmeric, ginger, holy basil, green tea, hu zhang, Chinese goldthread, barberry, oregano, and Baikal skullcap.
• The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties.
• In various preclinical studies, Zyflamend has been shown to suppress the expression of certain genes involved in the inflammatory response and in cancer progression, such as cyclooxygenase 1(COX-1), COX-2, 5-lipoxygenase (5-LOX), and 12-LOX.
• In other preclinical studies, Zyflamend demonstrated single-agent anticancer activity, and it improved cancer suppression when used with hormonal and chemotherapyagents.
• Results of a phase I study of Zyflamend suggest that use of this supplement is not associated with serious toxicity or adverse effects.

General information and history

Zyflamend is a dietary supplement that contains supercritical fluid (CO2) and hydroalcoholic extracts of the following herbs, combined and suspended in olive oil:

• Rosemary (Rosmarinus officinalis L.).
• Turmeric (Curcuma longa L.).
• Ginger (Zingiber officinale Roscoe).
• Holy basil (Ocimum sanctum L.).
• Green tea (Camellia sinensis [L.] Kuntze).
• Hu zhang (Polygonum cuspidatum Siebold & Zucc.).
• Chinese goldthread (Coptis chinensis Franch.).
• Barberry (Berberis vulgaris L.).
• Oregano (Origanum vulgare L.).
• Baikal skullcap (Scutellaria baicalensis Georgi).

The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of melanoma cells.[4]

The extracts in Zyflamend have been shown to have anti-inflammatory effects via inhibition of cyclooxygenase (COX) activity. COXs are enzymes that convert arachidonic acid into prostaglandins, which are thought to play a role in tumor development and metastasis. One COX enzyme, COX-2, is activated during chronic disease states, such as cancer.[5]

The antitumorigenic mechanisms of action of Zyflamend are unknown, but according to one study, Zyflamend may suppress activation of nuclear factor-kappa B (NF-kappa B) (a nuclear transcription factor involved in tumorigenesis) and NF-kappa B–regulated gene products.[6]

Preclinical/animal studies

In vitro studies

In a study reported in 2012, human prostate cancer cells were treated in vitro with Zyflamend. Cells treated with the supplement at concentrations ranging from 0.06 to 0.5 μL/mL exhibited dose-dependent decreases in androgen receptor and PSA expression levels compared with cells treated with the dimethyl sulfoxide vehicle control. Prostate cancer cells that were treated with a combination of Zyflamend (0.06 μL/mL) and bicalutamide (25 μM), an androgen receptor inhibitor, showed reductions in cell growth, PSA expression, and antiapoptotic protein expression compared with cells treated with Zyflamend or bicalutamide alone.[7]

Although the individual components of Zyflamend have been shown to influence COX activity, one study examined the effects of the drug on COX-1 and COX-2 expression in prostate cancer cells. The results revealed that Zyflamend, at a concentration of 0.9 μL/mL, inhibited expression of both COX-1 and COX-2. At a concentration of 0.45 μL/mL, the degree of COX-2 inhibition was observed, but the level of COX-1 inhibition was reduced by 50%. At a concentration of 0.1 μL/mL, Zyflamend effectively inhibited growth of prostate cancer cells and increased the level of caspase-3, a proapoptotic enzyme. However, a separate experiment indicated that the prostate cancer cells used in the study (LNCaP cells, which are androgen sensitive) did not express high levels of COX-2, suggesting that Zyflamend’s effects on prostate cancer cells may result from a COX-independent mechanism.[5]

The lipoxygenase isozymes 5-LOX and 12-LOX are also proteins associated with inflammation and tumor growth. In a 2007 study, the effects of Zyflamend on 5-LOX and 12-LOX expression were investigated. The findings indicated that 0.25 μL/mL to 2 μL/mL of Zyflamend produced decreases in 5-LOX and 12-LOX expression in PC3 prostate cancer cells (cells that have high metastatic potential). The supplement also inhibited cell proliferation and induced apoptosis. In addition, Zyflamend treatment resulted in a decrease in Rb phosphorylation (Rb proteins control cell-cycle -related genes). These results indicate that Zyflamend may inhibit prostate cancer cell growth through a variety of mechanisms.[8]

In a 2011 study, human prostate cancer cells were treated with Zyflamend (200 µg /mL). After 48 hours of treatment, a statistically significant reduction in cell growth was observed for Zyflamend-treated cells, compared with control cells (P < .005). In another experiment, prostate cancer cells were treated with insulin-like growth factor -1 (IGF-1; 0–100 ng /mL) alone or in combination with Zyflamend (200 µg/mL). Cells treated with IGF-1 alone exhibited statistically significant, dose-dependent increases in cell proliferation, whereas cells treated with both IGF-1 and Zyflamend showed significant decreases in cell proliferation. Zyflamend was also shown to decrease cellular levels of the IGF-1 receptor and the androgen receptor in prostate cancer cells.[9] A 2014 investigation by this team found that Zyflamend inhibits the expression of class I and class II histone deacetylases(HDAC) and upregulated their downstream target p21 suppressor gene.[10] The extracts of the individual components of the 10 botanicals in Zyflamend were also evaluated in an effort to identify which compounds contributed most to the inhibition of HDAC expression. Chinese goldthread and baikal skullcap appeared to be the most likely major contributors to the overall Zyflamend effect on HDAC expression.

Animal studies

Additional evidence that Zyflamend promotes apoptosis in cancer cells was obtained in laboratory and animal studies reported in 2012.[11] Treatment of human colorectalcarcinoma cell lines in vitro with Zyflamend was shown to significantly down regulate expression of antiapoptotic proteins, up regulate expression of Bax (a proapoptotic protein), and increase expression of death receptor 5 (DR5), a receptor important in apoptosis. Moreover, when nude mice with pancreatic cancer cell implants were randomly assigned to receive Zyflamend or a control treatment for 4 weeks, tumor cells from the Zyflamend-treated mice showed significant reductions in antiapoptotic proteins and significantly increased expression of DR5, compared with tumor cells from control-treated animals.

In a 2011 study, mice were also implanted with pancreatic cancer cells and then treated with gemcitabine and/or Zyflamend. The combination treatment resulted in a significantly greater decrease in tumor growth than did treatment with gemcitabine or Zyflamend alone. Other findings from this study suggest that Zyflamend exerted its effects by sensitizing the pancreatic tumors to gemcitabine through suppression of multiple targets linked to tumorigenesis.[12]

Human studies

Intervention studies

In one case report, a patient with HGPIN received Zyflamend 3 times daily for 18 months. Zyflamend did not affect this patient's PSA level, but, after 18 months, repeat core biopsiesof the prostate did not show PIN or cancer.[13]

In a 2009 phase I study designed to assess safety and toxicity, patients with HGPIN were assigned to take Zyflamend (780 mg) 3 times daily for 18 months, plus combinations of dietary supplements (i.e., probiotic supplement, multivitamin, green and white tea extract, Baikal skullcap, docosahexaenoic acid, holy basil, and turmeric). Zyflamend and the additional dietary supplements were well tolerated by the patients, and no serious adverse events occurred. After 18 months of treatment, 60% of the study subjects had only benigntissue at biopsy; 26.7% had HGPIN in one core; and 13.3% had prostate cancer.[14]

Adverse effects

Zyflamend was well tolerated in the previously described 2009 clinical study. Mild heartburn was reported in 9 of 23 subjects, but it resolved when the study supplements were taken with food. No serious toxicity or adverse events were reported in the study.[14]

References

1. Thomas R, Williams M, Sharma H, et al.: A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer--the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis 17 (2): 180-6, 2014. [PUBMED Abstract]
2. Gontero P, Marra G, Soria F, et al.: A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"? Prostate 75 (11): 1177-86, 2015. [PUBMED Abstract]
3. Paur I, Lilleby W, Bøhn SK, et al.: Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA. Clin Nutr 36 (3): 672-679, 2017. [PUBMED Abstract]
4. Ekmekcioglu S, Chattopadhyay C, Akar U, et al.: Zyflamend mediates therapeutic induction of autophagy to apoptosis in melanoma cells. Nutr Cancer 63 (6): 940-9, 2011. [PUBMED Abstract]
5. Bemis DL, Capodice JL, Anastasiadis AG, et al.: Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. Nutr Cancer 52 (2): 202-12, 2005. [PUBMED Abstract]
6. Sandur SK, Ahn KS, Ichikawa H, et al.: Zyflamend, a polyherbal preparation, inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products. Nutr Cancer 57 (1): 78-87, 2007. [PUBMED Abstract]
7. Yan J, Xie B, Capodice JL, et al.: Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth. Prostate 72 (3): 244-52, 2012. [PUBMED Abstract]
8. Yang P, Cartwright C, Chan D, et al.: Zyflamend-mediated inhibition of human prostate cancer PC3 cell proliferation: effects on 12-LOX and Rb protein phosphorylation. Cancer Biol Ther 6 (2): 228-36, 2007. [PUBMED Abstract]
9. Huang EC, Chen G, Baek SJ, et al.: Zyflamend reduces the expression of androgen receptor in a model of castrate-resistant prostate cancer. Nutr Cancer 63 (8): 1287-96, 2011. [PUBMED Abstract]
10. Huang EC, Zhao Y, Chen G, et al.: Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells. BMC Complement Altern Med 14: 68, 2014. [PUBMED Abstract]
11. Kim JH, Park B, Gupta SC, et al.: Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through up-regulation of death receptors and down-regulation of survival proteins: role of ROS-dependent CCAAT/enhancer-binding protein-homologous protein pathway. Antioxid Redox Signal 16 (5): 413-27, 2012. [PUBMED Abstract]
12. Kunnumakkara AB, Sung B, Ravindran J, et al.: Zyflamend suppresses growth and sensitizes human pancreatic tumors to gemcitabine in an orthotopic mouse model through modulation of multiple targets. Int J Cancer 131 (3): E292-303, 2012. [PUBMED Abstract]
13. Rafailov S, Cammack S, Stone BA, et al.: The role of Zyflamend, an herbal anti-inflammatory, as a potential chemopreventive agent against prostate cancer: a case report. Integr Cancer Ther 6 (1): 74-6, 2007. [PUBMED Abstract]
14. Capodice JL, Gorroochurn P, Cammack AS, et al.: Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial. J Soc Integr Oncol 7 (2): 43-51, 2009. [PUBMED Abstract]