Muscadine Grape Skin Extract (MPX) in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial

Epithelial–mesenchymal transition (EMT), a key event in cancer metastasis, allows polarized epithelial cells to assume mesenchymal morphologies, enhancing invasiveness and migration, and can be induced by reactive oxygen species (ROS). Val16A (Ala) SOD2 polymorphism has been associated with increased prostate cancer (PCa) risk. We hypothesized that SOD2 Ala single nucleotide polymorphism (SNP) may promote EMT. We analyzed SOD2 expression and genotype in various prostate cell lines. Stable overexpression of Ala-SOD2 or Val-SOD2 allele was performed in Lymph Node Carcinoma of the Prostate (LNCaP) cells followed by analysis of intracellular ROS and EMT marker protein expression. Treatments were performed with muscadine grape skin extract (MSKE) antioxidant, with or without addition of H2O2 to provide further oxidative stress. Furthermore, MTS cell proliferation, cell migration, and apoptosis assays were completed. The results showed that SOD2 expression did not correlate with tumor aggressiveness nor SOD2 genotype. We demonstrated that the Ala-SOD2 allele was associated with marked induction of EMT indicated by higher Snail and vimentin, lower E-cadherin, and increased cell migration, when compared to Val-SOD2 allele or Neo control cells. Ala-SOD2 SNP cells exhibited increased levels of total ROS and superoxide and were more sensitive to co-treatment with H2O2 and MSKE, which led to reduced cell growth and increased apoptosis. Additionally, MSKE inhibited Ala-SOD2 SNP-mediated EMT. Our data indicates that treatment with a combination of H2O2-generative drugs, such as certain chemotherapeutics and antioxidants such as MSKE that targets superoxide, hold promising therapeutic potential to halt PCa progression in the future.

Download Full-text

Muscadine grape skin extract reverts snail-mediated epithelial mesenchymal transition via superoxide species in human prostate cancer cells

BMC Complementary and Alternative Medicine ◽

10.1186/1472-6882-14-97 ◽

2014 ◽

Vol 14 (1) ◽

Cited By ~ 17

Author(s):

Liza J Burton ◽

Petrina Barnett ◽

Basil Smith ◽

Rebecca S Arnold ◽

Tamaro Hudson ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Human Prostate ◽

Skin Extract ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Grape Skin ◽

Mesenchymal Transition ◽

Grape Skin Extract

Download Full-text

A phase I trial of muscadine grape skin in men with biochemically recurrent prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.263 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 263-263

Author(s):

Channing Judith Paller ◽

Michelle A. Rudek ◽

Emmanuel S. Antonarakis ◽

Mario A. Eisenberger ◽

Hans J. Hammers ◽

...

Keyword(s):

Prostate Cancer ◽

Phase I ◽

Phase Ii ◽

Phase Ii Trial ◽

High Dose ◽

Recurrent Prostate Cancer ◽

Grape Skin ◽

Study Results ◽

Patient Reported ◽

Muscadine Grape

263 Background: New therapies are being explored as an alternative to observation in men with biochemically recurrent prostate cancer (BRPC). Muscadine Grape Skin (MPX) is comprised of ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. Here we summarize data from a phase I dose finding trial. Methods: This phase I study assigned non-metastatic BRPC patients to increasing doses of MPX (Muscadine Naturals) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Dose selection is based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. Our primary end point was to determine the recommended phase II dosing. We calculated changes in prostate-specific antigen (PSA) doubling time (PSADT) from at least three measurements prior to trial initiation and PSA measurements on study. Results: The cohort (n=14, 71% white, 29% black) had a median follow-up of 14.7 (6.9 to 20.7) months, median age 61, median Gleason seven, and median PSA of 5.1 ng/mL (0.2 to 153.4). Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 burping. No other related adverse events were reported and one patient reported improvement of chronic constipation. Two of 14 patients came off study for metastatic disease. Median within-patient PSADT increased from 9.4 to 12.3 months with a PSADT difference of 3.9 months. Conclusions: These data suggest that 4,000 mg of MPX is safe, and exploratory review of change in PSADT suggests there is enough data to proceed to a phase II trial. Both low dose (500 mg) and high dose (4,000 mg) MPX are being further investigated in a multicenter, placebo-controlled, dose evaluating phase II trial. Clinical trial information: NCT01317199.

Download Full-text

Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells

Carcinogenesis ◽

10.1093/carcin/bgv084 ◽

2015 ◽

Vol 36 (9) ◽

pp. 1019-1027 ◽

Cited By ~ 29

Author(s):

Liza J. Burton ◽

Basil A. Smith ◽

Bethany N. Smith ◽

Quentin Loyd ◽

Peri Nagappan ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cathepsin L ◽

Skin Extract ◽

Grape Skin ◽

Muscadine Grape ◽

Grape Skin Extract

Download Full-text

Muscadine Grape Skin Extract Induces an Unfolded Protein Response-Mediated Autophagy in Prostate Cancer Cells: A TMT-Based Quantitative Proteomic Analysis

PLoS ONE ◽

10.1371/journal.pone.0164115 ◽

2016 ◽

Vol 11 (10) ◽

pp. e0164115 ◽

Cited By ~ 21

Author(s):

Liza J. Burton ◽

Mariela Rivera ◽

Ohuod Hawsawi ◽

Jin Zou ◽

Tamaro Hudson ◽

...

Keyword(s):

Prostate Cancer ◽

Unfolded Protein Response ◽

Cancer Cells ◽

Proteomic Analysis ◽

Skin Extract ◽

Prostate Cancer Cells ◽

Grape Skin ◽

Unfolded Protein ◽

Protein Response ◽

Grape Skin Extract

Download Full-text

A phase II study of muscadine grape skin extract in men with biochemically recurrent prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.248 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 248-248

Author(s):

Channing Judith Paller ◽

Elisabeth I. Heath ◽

Mary-Ellen Taplin ◽

Mark N. Stein ◽

Glenn J. Bubley ◽

...

Keyword(s):

Prostate Cancer ◽

Gleason Score ◽

Therapeutic Option ◽

High Dose ◽

Skin Extract ◽

Antitumor Effects ◽

Significant Treatment ◽

Grape Skin ◽

Intention To Treat ◽

Muscadine Grape

248 Background: Pulverized muscadine grape ( Vitis rotundifolia) skin (MPX) is a potential therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy. MPX demonstrated antitumor effects in PCa through antioxidant activity of its principal polyphenol components, ellagic acid, quercetin, and resveratrol. A Phase I trial demonstrated safety of MPX in doses up to 4000 mg/day. Methods: This is a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX (manufactured by Muscadine Naturals Inc. in Warsaw, NC) in 125 men with BCR PCa. Participants were stratified by baseline PSADT and Gleason score, with no restrictions for PSADT and no upper limit PSA value. Patients were randomly assigned 2:2:1 to receive 4000 mg (8 capsules) of MPX, 500 mg (1 capsule) of MPX plus 7 capsules of placebo, or 8 capsules of placebo. PSA levels were obtained every 3 months The trial was powered to detect a statistically significant between-group difference of around 6 months (low dose) and 12 months (high dose) in PSADT relative to placebo. Results: The intention to treat (ITT) population included 116 patients, of which 97% were treated for up to 6 and 58% were treated for up to 12 months. This ITT population was 79% white, with median age 68 years, 47% with Gleason score ≤ 6 or 3+4, and 12% with ECOG status of 1. Median PSADT in the ITT population lengthened from 7.5 months at baseline (range 1.4 to 74.6) to 9.8 months after treatment (range 2.3 to 151.5) (p < 0.001). There was no significant treatment difference in PSADT between the control and the treatment groups (p = 0.84). Eighteen percent (21/116) of men had a post-baseline PSADT of more than 200% of baseline. No clinically significant toxicities were seen. Conclusions: These data suggest that both 500 and 4000 mg of MPX are safe. The lengthening PSADT in patients treated with MPX is not significantly greater than that provided by placebo. A subgroup analysis of patients more likely to benefit (those with the AA genotype of MnSOD) is ongoing. Clinical trial information: NCT01317199.

Download Full-text