Oxidative stress is a key factor in the development of many diseases including cancer. Antioxidants prevent cellular damage by neutralizing free radicals and are being investigated as potential therapeutic strategies against cancer. In this installment of The ASCO Post’s Integrative Oncology series, Nicholas I. Simon, MD, and Channing J. Paller, MD, summarize the available findings on the effects of muscadine grape skin extract, a natural product with antioxidant and anti-inflammatory properties, in patients with prostate cancer.

Nicholas I. Simon, MD

Channing J. Paller, MD

Overview

Oxidative stress plays a role in the development and progression of prostate cancer, which has led to exploring antioxidants as therapeutic agents.^1,2 One potential option of significant interest is muscadine grape skin extract (grape extract). Muscadine grapes have a high concentration of polyphenols, which have antioxidant and anti-inflammatory properties.³

Preclinical studies have proposed several mechanisms through which grape extract may affect prostate cancer cells. Hudson et al demonstrated that prostate cancer cell lines treated with grape extract led to downregulation of the PI3K-Akt pathway, leading to apoptosis.⁴ Furthermore, in metastatic prostate cancer cell lines, grape extract inhibited migration and invasion.⁵ Sweeney et al demonstrated that grape extract also inhibited the epithelial-mesenchymal transition of prostate cancer cells, thereby reducing their invasive potential.⁶

Clinical Studies

These findings led to a phase I study in men with biochemically recurrent prostate cancer to evaluate the safety and tolerability of MPX, a pulverized muscadine grape skin extract.⁷ The study found that MPX at the highest dose tested was both safe and tolerable, with no dose-limiting toxicities. Similarly, another phase I study looking at patients with metastatic and unresectable cancers treated with muscadine grape extract found that it was safe and well tolerated, including among those patients with a poor performance status.⁸

However, a phase II study conducted to determine the efficacy of MPX in patients with biochemically recurrent prostate cancer⁹ was negative, with no significant differences seen across treatment groups for the primary endpoint of change in prostate-specific antigen (PDS) doubling time (P = .81). Similarly, a phase II trial looking at pomegranate extract, another antioxidant-rich supplement, also failed to demonstrate a significant change in PSA doubling time in patients with biochemically recurrent disease when compared with placebo.¹⁰ Although these studies did not find benefits of grape extract or pomegranate extract in treating patients with biochemically recurrent disease in a nonselected population, interestingly, they identified potential biomarker subgroups that may benefit.

GUEST EDITOR

Jun J. Mao, MD, MSCE

Dr. Mao is the Laurance S. Rockefeller Chair in Integrative Medicine and Chief of Integrative Medicine Service at Memorial Sloan Kettering Cancer Center, New York.

Potential Role in Specific Populations

Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme with antioxidant properties, responsible for breaking down reactive oxygen species. Polymorphisms in this gene exist, with either a valine (V) or alanine (A) present at codon 16.¹¹ The AA genotype, present in 20% to 50% of the population, had previously been shown to lead to the toxic buildup of hydrogen peroxide and is associated with a higher risk for aggressive prostate cancer.^12,13

The phase II MPX study demonstrated that the patients with biochemically recurrent disease with MnSOD AA treated with MPX had significantly prolonged PSA doubling times, whereas the placebo group did not—a finding mirrored in the pomegranate trial. These results indicate that antioxidant therapy with MPX may only be effective in the high risk MnSOD AA population. Furthermore, research shows that in the presence of long-term low-lycopene antioxidant status, men with an AA genotype had a threefold increase in aggressive prostate cancer risk compared with men who had an AV or VV genotype.¹⁴

Next Steps

A phase III trial is currently underway examining the effect of MPX on PSA doubling time in patients with biochemically recurrent disease who test positive for the AA polymorphism (ClinicalTrials.gov identifier NCT03535675). The final results of this trial should help to determine the role of grape extract in treating patients with biochemically recurrent disease. The early data and minimal side-effect profile make this an interesting option that may allow specific populations of high-risk men to treat their prostate cancer while deferring the significant quality-of-life effects associated with the initiation of androgen-deprivation therapy.

DISCLOSURE: Dr. Simon and Dr. Paller reported no conflicts of interest.

REFERENCES

1. Khandrika L, et al: Cancer Lett 282:125-136, 2009.

2. Nelson WG, et al: N Engl J Med 349:366-381, 2003.

3. Yi W, et al: J Agric Food Chem 53:8804-8812, 2005.

4. Hudson TS, et al: Cancer Res 67:8396-8405, 2007.

5. Ignacio DN, et al: Heliyon 5:e01128, 2019.

6. Sweeney JD, et al: Antioxidants (Basel) 10:213, 2021.

7. Paller CJ, et al: Prostate 75:1518-1525, 2015.

8. Bitting RL, et al: Am J Clin Oncol 44:239-246, 2021.

9. Paller CJ, et al: Clin Cancer Res 24:306-315, 2018.

10. Pantuck AJ, et al: Prostate Cancer Prostatic Dis 18:242-248, 2015.

11. Li H, et al: Cancer Res 65:2498-2504, 2005.

12. Wang S, et al: Eur J Cancer 45:2874-2881, 2009.

13. Li X, et al: Int J Biol Markers 31:e422-e430, 2016.

14. Mikhak B, et al: Carcinogenesis 29:2335-2340, 2008.