domingo, 7 de julio de 2019

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)—Health Professional Version - National Cancer Institute 4/10

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

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

Modified Citrus Pectin

Overview

This section contains the following key information:
  • Citrus pectin (CP) is a complex polysaccharide found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.
  • Preclinical research suggests that modified citrus pectin (MCP) may have effects on cancer growth and metastasis through multiple potential mechanisms.
  • Very limited clinical research has been done with a couple of CP-containing products. For prostate cancer patients, the results suggest some potential clinical benefits with relatively minor and infrequent adverse events.

General Information and History

Pectin is a complex polysaccharide contained in the primary cell walls of terrestrial plants. The word ‘pectin’ comes from the Greek word for congealed or curdled. Plant pectin is used in food processing as a gelling agent and also in the formulation of oral and topicalmedicines as a stabilizer and nonbiodegradable matrix to support controlled drug delivery.[1] CP is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.[2] Modification results in shorter molecules that dissolve better in water and are more readily absorbed by the body than are complex, longer chain CPs.[3] One of the molecular targets of MCP is galectin-3, a protein found on the surface and within mammalian cells that is involved in many cellular processes, including cell adhesion, cell activation and chemoattraction, cell growth and differentiation, the cell cycle, and apoptosis; MCP inhibits galectin-3 activity.[2]
Some research suggests that MCP may be protective against various types of cancer, including colon, lung, and prostate cancer. MCP may exert its anticancer effects by interfering with tumor cell metastasis or by inducing apoptosis.[4]
MCP was also shown to activate natural killer cells in leukemic cell cultures, suggesting it may be able to stimulate the immune system.[5]

Preclinical Studies/Animal Studies

In vitro studies

In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; CP, Pectasol (PeS, a dietary supplementcontaining MCP), and fractionated pectin powder (FPP). FPP induced apoptosis to a much greater degree than did CP and PeS. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP. This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.[4]
In a 2010 study, prostate cancer cells were treated with PeS or PectaSol-C, the only two MCPs previously used in human trials. The researchers postulated that, because it has a lower molecular weight, PectaSol-C may have better bioavailability than PeS. Both types of MCP were tested at a concentration of 1 mg/mL and both were effective in inhibiting cell growth and inducing apoptosis through inhibition of the MAPK/ERK signaling pathway and activation of the enzyme caspase-3.[6]
In one study, the role of galectin-3, a multifunctional endogenous lectin, in cisplatin -treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 (via silencing RNA knockdown of galectin-3 expression or treatment with MCP) were susceptible to cisplatin-induced apoptosis. These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the efficacyof cisplatin treatment in prostate cancer may be improved by inhibiting galectin-3.[7]

Animal studies

Only a few studies have been reported on the effects of MCP in animals bearing implantedcancers and only one involving prostate cancer.[8,9] The prostate cancer study examined the effects of MCP on the metastasis of prostate cancer cells injected into rats. In the study, rats were given 0.0%, 0.01%, 0.1%, or 1.0% MCP (wt/vol) in their drinking water beginning 4 days after cancer cell injection. The analysis revealed that treatment with 0.1% and 1.0% MCP resulted in statistically significant reductions in lung metastases but did not affect primary tumor growth.[9]

Human Studies

Intervention studies

In a 2007 pilot study, patients with advanced solid tumors (various types of cancers were represented, including prostate cancer) received MCP (5 g MCP powder dissolved in water) 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of quality of life, including physical functioning, global health status, fatigue, pain, and insomnia. In addition, 22.5% of participants had stable disease after 8 weeks of MCP treatment, and 12.3% of participants had disease stabilization lasting more than 24 weeks.[3]
The effect of MCP on prostate-specific antigen (PSA) doubling time (PSADT) was investigated in a 2003 study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day (totaling 14.4 g of MCP powder/d) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (P ≤ .05) increase in PSADT.[10]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

In one prospective pilot study, MCP was well tolerated by the majority of treated patients, with the most commonly reported side effects being pruritus, dyspepsia, and flatulence.[3] In another study, no serious side effects from MCP were reported, although three patients withdrew from the study due to abdominal cramps and diarrhea that improved once treatment was halted.[10]
References
  1. Mohnen D: Pectin structure and biosynthesis. Curr Opin Plant Biol 11 (3): 266-77, 2008. [PUBMED Abstract]
  2. Glinsky VV, Raz A: Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res 344 (14): 1788-91, 2009. [PUBMED Abstract]
  3. Azemar M, Hildenbrand B, Haering B, et al.: Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clin Med Oncol 1: 73-80, 2007. Available online. Last accessed September 13, 2017.
  4. Jackson CL, Dreaden TM, Theobald LK, et al.: Pectin induces apoptosis in human prostate cancer cells: correlation of apoptotic function with pectin structure. Glycobiology 17 (8): 805-19, 2007. [PUBMED Abstract]
  5. Ramachandran C, Wilk BJ, Hotchkiss A, et al.: Activation of human T-helper/inducer cell, T-cytotoxic cell, B-cell, and natural killer (NK)-cells and induction of natural killer cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin. BMC Complement Altern Med 11: 59, 2011. [PUBMED Abstract]
  6. Yan J, Katz A: PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells. Integr Cancer Ther 9 (2): 197-203, 2010. [PUBMED Abstract]
  7. Wang Y, Nangia-Makker P, Balan V, et al.: Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death Dis 1: e101, 2010. [PUBMED Abstract]
  8. Hayashi A, Gillen AC, Lott JR: Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice. Altern Med Rev 5 (6): 546-52, 2000. [PUBMED Abstract]
  9. Pienta KJ, Naik H, Akhtar A, et al.: Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 87 (5): 348-53, 1995. [PUBMED Abstract]
  10. Guess BW, Scholz MC, Strum SB, et al.: Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis 6 (4): 301-4, 2003. [PUBMED Abstract]

Pomegranate

Overview

This section contains the following key information:
  • The pomegranate (Punica granatum L.) is native to Asia and cultivated widely throughout world.
  • Various components of the pomegranate fruit contain minerals and bioactive polyphenolic compounds, in particular structurally distinct ellagitannins and derivatives, such as alpha-/beta-punicalagin, punicalin, and punigluconin.
  • Pomegranate juice and extract, as well as some of their bioactive components, inhibit the proliferation of various prostate cancer cell lines in vitro and induce apoptotic celldeath in a dose-dependent manner.
  • Cytochrome P450 enzyme inhibition and effects on insulin-like growth factor binding protein -3 (IGFBP-3) have been identified as being involved in the in vitro activity.
  • Studies in rodent models of prostate cancer have shown that ingestion of pomegranate juice can decrease the rate of development, growth, and spread of prostate cancer.
  • The only fully reported clinical trial of the use of pomegranate juice in men with prostate cancer showed that, on average, study participants who drank the juice had an increase in their prostate-specific antigen (PSA) doubling time (PSADT).
  • No serious adverse effects have been reported in clinical trials of pomegranate juice administration (8 oz per day for up to 33 months).
  • A phase II study reported that pomegranate extract was associated with an increase of at least 6 month in PSADT in both treatment arms (different doses), without adverse effects. However, a phase III placebo-controlled trial of pomegranate juice and extract did not show a significant increase in PSADT.

General Information and History

The pomegranate tree (Punica granatum L.) is a member of the Punicaceae family native to Asia (from Iran to northern India) and cultivated throughout the Mediterranean, Southeast Asia, the East Indies, Africa, and the United States.[1] The history of the pomegranate goes back centuries—the fruit is considered sacred by many religions and has been used for medicinal purposes since ancient times.[2] The fruit is comprised of peel (pericarp), seeds, and aril (outer layer surrounding the seeds). The peel makes up 50% of the fruit and contains minerals and a number of bioactive polyphenolic compounds, in particular structurally distinct ellagitannins and derivatives, such as alpha-/beta-punicalagin, punicalin, and punigluconin. The arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoids present in arils, are responsible for the red color of the fruit and its juice.[3] The majority of antioxidant activity comes from ellagitannins.[4] It has been shown that conversion of pomegranate ellagitannins by gut microbes produces a variety of metabolites, such as the urolithins.[5]
Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including cardiovascular disease,[6] and may also have positive effects on oralor dental health.[7]

Preclinical Studies/Animal Studies

Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.
In vitro studies
Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic acid, and then to urolithin A (UA) derivatives. According to a tissue distribution experiment in wild-type mice, the prostate gland rapidly takes up high concentrations of UA after oral or intraperitoneal administration (0.3 mg/mouse/dose). Ellagic acid (EA) was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8 mg/mouse/dose).[8]
Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[9-12] In one study, dihydrotestosterone -stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0–100 µM).[10] Four of the 13 compounds, epigallocatechin gallate (EGCG), delphinidin chloride, kaempferol, and punicic acid, exhibited an ability to inhibit cell growth in a dose-dependent manner. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid (a major constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggested that punicic acid may activate apoptosis by a caspase-dependent pathway.[10]
Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells in vitro.[11,13,14] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and DU-145) were treated with pomegranate polyphenols [punicalagin (PA) or EA], a pomegranate extract (POMx, which contains EA and PA), or pomegranate juice (PJ, which contains PA, EA, and anthocyanins) in concentrations ranging from 3.125 to 50 µg/mL (standardized to PA content). All four treatments resulted in statistically significantincreases in apoptosis and dose-dependent decreases in cell proliferation in the three cell lines. However, PJ and POMx were stronger inhibitors of cell growth than were PA and EA. In this study, the effects of PA, EA, POMx, and PJ on the expression of androgen -synthesizing enzyme genes and the androgen receptor were also measured. Although statistically significant decreases in gene expression occurred in LNCaP cells following treatment with POMx and in DU-145 cells following treatment with EA and POMx, significant decreases in gene expression and androgen receptor occurred in LNCaP-AR cells following all of the treatments.[11] In a second study, treating PC3 cells (human prostate cancer cells with a high metastatic potential) with POMx (10–100 µg/mL) resulted in cell growth inhibition and apoptosis, both in a dose-dependent manner. Treatment of CWR22Rv1 cells (prostate cancer cells that express the androgen receptor and secrete PSA) with POMx (10–100 µg/mL concentrations of pomegranate fruit extract) led to the inhibition of cell growth, a dose-dependent decrease in androgen receptor protein expression, and dose-dependent reductions in PSA protein levels.[14]
The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anticarcinogenic targets. In a study reported in 2009, the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined. In this study, urolithins A and B inhibited CYP1B1 expression and activity.[15]
In addition, the insulin-like growth factor (IGF) system has been implicated in prostate cancer. A study reported in 2010 examined the effects of a POMx on the IGF system. Treating LAPC4 prostate cancer cells with POMx (10 µg/mL concentration of pomegranate extract prepared from skin and arils minus seeds) resulted in cell growth inhibition and apoptosis, but treating the cells with both reagents led to larger effects on growth inhibition and apoptosis. However, these substances may have induced apoptosis by different mechanisms. Other findings suggested that POMx treatment reduced mTORphosphorylation at Ser2448 and Ser2481, whereas IGFBP-3 increased phosphorylation at those sites. In addition, CWR22Rv1 cells treated with POMx (1 and 10 µg/mL) exhibited a dose-dependent reduction in IGF1 mRNA levels, but treatment with IGFBP-3 or IGF-1 did not alter levels of IGF1; these results suggest that one way POMx decreases prostate cancer cell survival is by inhibiting IGF1 expression.[13]
In a study reported in 2011, human hormone -independent prostate cancer cells (DU145 and PC3 cell lines) were treated with 1% or 5% PJ for times ranging from 12 to 72 hours. The results showed that treatment with PJ increased adhesion and decreased the migration of prostate cancer cells. Molecular analyses revealed that PJ increased the expression of cell-adhesion related genes and inhibited the expression of genes involved in cytoskeletal function and cellular migration. These findings suggested that PJ may be beneficial in slowing down or preventing cancer cell metastasis. [16]
Animal studies
The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, athymic nude mice were injected with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ (0.1% or 0.2% POMx in drinking water, which resulted in an intake corresponding to 250 or 500 mL of PJ per day for an average adult human). Small, solid tumors appeared earlier in mice drinking normal water only than in mice drinking PJ (8 days vs. 11–14 days). Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in serum PSA levels compared with animals drinking normal water only.[14] In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[8,17]
Similarly, when nude mice were injected with pomegranate seed oil (2 µg/g body weight), pomegranate pericarp (peel) polyphenols (2 µg/g body weight), or saline 5 to 10 minutes before being implanted with solid prostate cancer tumors, mice injected with the pomegranate extracts had significantly smaller tumor volumes compared with the mice injected with saline (P < .001).[9]
In a study reported in 2011, 6-week-old transgenic adenocarcinoma of the mouse prostate (TRAMP) mice received normal drinking water or PJ (0.1% or 0.2% POMx in drinking water) for 28 weeks. The results showed that 100% of the mice that received water only developed tumors by age 20 weeks, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By age 34 weeks, 90% of the water-fed mice exhibited metastases to distant organs whereas only 20% of the mice that received pomegranate juice showed metastasis. The PJ-supplemented mice exhibited significantly increased life spans compared with the water-fed mice.[18]

Human Studies

Three clinical studies have examined the effect of interventions with pomegranate products on changes in PSADT in patients with biochemically recurrent prostate cancer who had a rising PSA after surgery or radiation therapy for presumed localized cancer.[19] The first study was a single-arm trial of 48 patients who drank 8 ounces (570 mg/d total polyphenol gallic acid equivalents) of PJ for up to 33 months. PSADT rose from a mean of 15 months (±11 months) at baseline to a mean of 54 months (±102 months, P < .001) on treatment (with a twofold increase in median PSADT from 11.8 to 24 months, P = .029).[20]
The second phase II study was published in 2013 and randomly assigned 92 patients to either 1 g (polyphenol gallic acid content equivalent to 8 ounces of pomegranate juice [47 patients]) or 3 g (45 patients) of pomegranate extract powder for up to 18 months. Overall, median PSADT increased from 11.9 to 18.5 months (P < .001), but no dose effect was seen (P = .554). Median PSADT increased from 11.9 to 18.8 months in the low-dose arm and from 12.2 to 17.5 months in the high-dose arm.[21]
The third trial was a randomized, double-blinded, placebo controlled study published in 2015. Of the 183 patients who enrolled, 64 patients were treated with placebo, 17 patients were treated with PJ, and 102 patients were treated with pomegranate liquid extract, which contained the same compounds found in PJ, with the exception of a higher proportional content of pomegranate polyphenol and a lower anthocyanidin content. The median change in PSADT was 4.5 months for the placebo group, 1.6 months for the extract group, and 7.6 months for the juice group; however, no paired comparison of groups was statistically significant.[22]
The differences in results between the trials may be partly because of less aggressive disease in the 2006 patient population with lower starting PSA values, but may also be because the first two trials lacked a placebo arm. All three trials found that pomegranate extract was safe to consume. Of note, in both the 2006 and 2013 studies, two patients in each trial had a 50% decline in PSA. In light of these findings, researchers wondered if there may be a sensitive subpopulation that might benefit from PJ. One potential genetic biomarker candidate is manganese superoxide dismutase (MnSOD), which is the primary antioxidant enzyme in mitochondria. A polymorphism at codon 16 of the MnSOD gene in men encodes either alanine (A) or valine (V). The AA genotype has been associated with more aggressive prostate cancer and with more sensitivity to antioxidants than the VA or VV genotype.[23] A preplanned subset analysis in the 2015 study of the 34 (22%) men with MnSOD AA genotype demonstrated a greater PSADT lengthening in the liquid extract group (median PSADT increased from 13.6 months to 25.6 months, P = .03) while no significant change was seen in the placebo group of MnSOD (median PSADT increased from 10.9–12.7 months, P = .22). In summary, the finding that men with the AA genotype who received pomegranate extract had greater lengthening of PSADT than did men in the placebo arm, along with the safe profile of PJ and extract in three large studies, suggest that there may be benefit in further studies in the AA MnSOD subpopulation.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.[20]
In a pilot study reported in 2007, the safety of PJ in patients with erectile dysfunction was examined. No serious adverse effects were observed during this study, and no participant dropped out due to adverse side effects. In the analysis of the results, no statistical comparisons were made of the adverse side effects observed in the intervention arm and the placebo arm.[24]
References
  1. Jurenka JS: Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev 13 (2): 128-44, 2008. [PUBMED Abstract]
  2. Langley P: Why a pomegranate? BMJ 321 (7269): 1153-4, 2000. [PUBMED Abstract]
  3. Viuda-Martos M, Fernandez-Lopez J, Perez-Alvarez JA: Pomegranate and its many functional components as related to human health: a review. Compr Rev Food Sci Food Saf 9 (6): 635-54, 2010. Available online. Last accessed September 13, 2017.
  4. Basu A, Penugonda K: Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 67 (1): 49-56, 2009. [PUBMED Abstract]
  5. Yuan T, Ma H, Liu W, et al.: Pomegranate's Neuroprotective Effects against Alzheimer's Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites. ACS Chem Neurosci 7 (1): 26-33, 2016. [PUBMED Abstract]
  6. Aviram M, Rosenblat M, Gaitini D, et al.: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr 23 (3): 423-33, 2004. [PUBMED Abstract]
  7. Menezes SM, Cordeiro LN, Viana GS: Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother 6 (2): 79-92, 2006. [PUBMED Abstract]
  8. Seeram NP, Aronson WJ, Zhang Y, et al.: Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem 55 (19): 7732-7, 2007. [PUBMED Abstract]
  9. Albrecht M, Jiang W, Kumi-Diaka J, et al.: Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7 (3): 274-83, 2004. [PUBMED Abstract]
  10. Gasmi J, Sanderson JT: Growth inhibitory, antiandrogenic, and pro-apoptotic effects of punicic acid in LNCaP human prostate cancer cells. J Agric Food Chem 58 (23): 12149-56, 2010. [PUBMED Abstract]
  11. Hong MY, Seeram NP, Heber D: Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor. J Nutr Biochem 19 (12): 848-55, 2008. [PUBMED Abstract]
  12. Lansky EP, Jiang W, Mo H, et al.: Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 23 (1): 11-20, 2005. [PUBMED Abstract]
  13. Koyama S, Cobb LJ, Mehta HH, et al.: Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis. Growth Horm IGF Res 20 (1): 55-62, 2010. [PUBMED Abstract]
  14. Malik A, Afaq F, Sarfaraz S, et al.: Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A 102 (41): 14813-8, 2005. [PUBMED Abstract]
  15. Kasimsetty SG, Bialonska D, Reddy MK, et al.: Effects of pomegranate chemical constituents/intestinal microbial metabolites on CYP1B1 in 22Rv1 prostate cancer cells. J Agric Food Chem 57 (22): 10636-44, 2009. [PUBMED Abstract]
  16. Wang L, Alcon A, Yuan H, et al.: Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 3 (7): 742-54, 2011. [PUBMED Abstract]
  17. Sartippour MR, Seeram NP, Rao JY, et al.: Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. Int J Oncol 32 (2): 475-80, 2008. [PUBMED Abstract]
  18. Adhami VM, Siddiqui IA, Syed DN, et al.: Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. Carcinogenesis 33 (3): 644-51, 2012. [PUBMED Abstract]
  19. Paller CJ, Pantuck A, Carducci MA: A review of pomegranate in prostate cancer. Prostate Cancer Prostatic Dis 20 (3): 265-270, 2017. [PUBMED Abstract]
  20. Pantuck AJ, Leppert JT, Zomorodian N, et al.: Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12 (13): 4018-26, 2006. [PUBMED Abstract]
  21. Paller CJ, Ye X, Wozniak PJ, et al.: A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 16 (1): 50-5, 2013. [PUBMED Abstract]
  22. Pantuck AJ, Pettaway CA, Dreicer R, et al.: A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis 18 (3): 242-8, 2015. [PUBMED Abstract]
  23. Iguchi T, Wang CY, Delongchamps NB, et al.: Association of MnSOD AA Genotype with the Progression of Prostate Cancer. PLoS One 10 (7): e0131325, 2015. [PUBMED Abstract]
  24. Forest CP, Padma-Nathan H, Liker HR: Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: a randomized, placebo-controlled, double-blind, crossover study. Int J Impot Res 19 (6): 564-7, 2007 Nov-Dec. [PUBMED Abstract]
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