Agaricus bisporus Mushroom in Biochemically Recurrent Prostate Cancer

Review of a recent phase I trial

By Sara Thyr, ND

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Reference

Twardowski P, Kanaya N, Frankel P, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: roles of cytokines and myeloid-derived suppressor cells for agaricus bisporus–induced prostate-specific antigen responses. Cancer. 2015;121(17):2942-2950.

Design

This was a phase I, single-arm, unblended, single-facility trial.

Participants

The 36 male patients enrolled (mean age 68) had all been diagnosed with biochemically recurrent prostate cancer (BRPC). All had had prior radiation therapy, and 33 (92%) had also undergone earlier prostatectomy. Eleven patients (30%) also had undergone hormonal therapy. Their mean prostate-specific antigen (PSA) at the onset of therapy was 1.9 ng/ml. To be included in the study, patients had to demonstrate biochemical evidence of treatment failure through increasing PSA levels. They were excluded from the study if they showed clinical or radiographic evidence of metastatic disease.

Intervention

Patients were given white button mushroom (WBM) powder tablets twice a day until PSA progression, clinical progression, or toxicity. Six patients were separated into 6 mushroom dose cohorts: 4, 6, 8, 10, 12, and 14 g/day. If no patient among the dose cohort exhibited dose-limiting toxicity during a 28-day treatment cycle, the next higher dose was tested. 

Outcome Measures

The primary objective was to evaluate treatment feasibility and associated toxicity. The secondary objectives were to determine WBM’s effect on serum PSA/androgen levels, myeloid-derived suppressor cells (MDSCs), and cytokine levels. 

Results 

No study participant experienced dose-limiting toxicities. Four of the participants had a partial or complete response to the mushroom powder for an overall PSA response of 11% (95% confidence interval: 4%-26%). Two patients (at dosages of 8 and 14 g/day) experienced a prolonged complete response in which their PSA declined to undetectable levels and remained undetectable at least to the date when the article was submitted for publication, a response of 49 and 30 months. Two patients demonstrated a partial response in which their PSAs dropped to 50% of baseline. One of these patients had remained on the study for 39 months. The second partial responder maintained the decreased PSA for only 7 months. Five other patients showed no increase in PSA for the duration of the study. In addition to these partial and complete responders, 13 patients (36%) demonstrated some PSA decline after beginning therapy.

Immunological Factors

No definitive cytokine patterns were noted except for that of interleukin-15 (IL-15). Complete and partial responders had higher IL-15 levels at the beginning and after treatment. Overall IL-15 levels were not changed by treatment in the responders and nonresponders.

Practice Implications

This article should bring a small ray of optimism to those with biochemically recurrent prostate cancer (BRPC). While these mushroom tablets do not work all of the time, they work some of the time.
 
BRPC is defined by an increase in PSA in men who have already had definitive treatment for prostate cancer. Treatments included prostatectomy and/or radiation. In this study most of the participants had undergone both treatments.1
 
Within 10 to 15 years of therapy, 25% to 30% of all prostate cancer patients experience recurrence.1 Most of these study participants had already been treated with both surgery and radiation, leaving them few if any additional expectations for possible cure. In this setting of biological recurrence, the primary option offered will be androgen deprivation therapy. This choice will suppress prostate cancer, but it is not considered curative and typically is accompanied by significant undesirable side effects. These include “weight gain, muscle weakness, hot flashes, erectile dysfunction, loss of libido, increased risk of diabetes, and cardiovascular problems.”2
 
Androgen deprivation therapy also does not represent a potential cure, but rather a delay of disease recurrence. Its effect on overall survival is not clear. Because of this, the authors felt that it was worth investigating the potential of a minimally toxic oral therapy administered on an outpatient basis for BRPC that shows effectiveness against disease progression.
 
Mushrooms are not the only naturally occurring substances to affect the growth or spread of cancers. Several natural therapies have shown some promise in prostate cancer prevention, recurrence, and treatment, including pomegranate juice,3 modified citrus pectin,4 lycopene, and isoflavone.5 Yet none of these substances has been reported to reduce PSA to the extent seen in this trial. 
 
Mushrooms have been used medicinally for centuries, and many species have been shown to have anticancer properties.6 Mushroom has been shown to inhibit prostate cancer, colon cancer, and breast cancer cell lines.7 The authors of this current study are well known for earlier research demonstrating that WBMs act as aromatase inhibitors in women.8-9 In this paper they use their assay of aromatase inhibition to judge the potency of their mushroom powder. 

The White Button Mushroom

The mushroom used in this study—the white button mushroom (Agaricus bisporus) is the most common edible mushroom available in the United States. It is widely cultivated and readily available in grocery stores. Over half a billion pounds are cultivated annually in the United States. Evidence is mounting for the beneficial anticancer effect of the WBM. Isolated lectins have been shown to help chemotherapy for breast and colon cancer work more effectively by increasing the sensitivity of the cells being treated to the medication.10 They also decrease the proliferation of colon cancer cells and increase antioxidant function. Breast cancer cell proliferation was decreased because of inhibition of aromatase activity by WBM and some of its fractions, including conjugated linoleic acid. Prior research into WBM on prostate cancer cell lines proved that WBM extract inhibits cell proliferation largely by inducing apoptosis. It was because of this promising earlier research that the current trial was conceived. 
 
This study was to evaluate the feasibility, toxicity, and biological activity of prolonged treatment with WBM powder. By looking at immune modulators, cytokines, and MDSCs, the authors wanted to also find any biological differences between those patients whose PSA responded and those whose did not.

Immunosuppressive Cell Subset

MDSCs in peripheral blood from enrollment to week 13 were decreased in the patients who had complete and partial responses. Their levels dropped 78%, 45%, 94%, and 65%. There was no change in MDSCs in non-responders.
 
While IL-15 is studied on its own for cancer, it might not be ideal for single treatment. In these patients, it looks like the WBM strongly influenced the immune inhibition. Along with this, MDSCs play a role in inhibition of the immune system, and their reduction seems to unleash stronger cancer surveillance. MDSCs were dramatically reduced in the strongest responders. Recall that these men had the highest IL-15. 
 
While WBM lowers blood sugar and cholesterol in diabetic and hypercholesterolemic rats, significant changes in blood glucose and lipids have not been seen with humans treated with WBM.

Limitations

With just 36 patients enrolled, this study was relatively small. Repeating this dosage of WBM in a randomized, placebo-controlled setting is necessary to make a more definitive conclusion. 
 
In addition, much research on medicinal mushrooms uses hot water extracts as the preparation method of choice, since mushrooms are very high in chitin, which is difficult for the human body to break down and utilize. The authors’ initial research on WBM studied the aromatase activity of the water extract of the mushroom.11 But since for this study they utilized lyophilized (freeze-dried) whole WBM, it is unclear which aspect of the mushroom they were looking to assess and which component is the most beneficial for BRPC. In fact, it does not appear that aromatization was affected, since measurements of testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA) throughout the study were unchanged. Future studies should include an arm for the freeze-dried mushroom as well as a hot water-derived extract, in order to compare them. It would also be worthwhile to assess which of the components with known medicinal activity were highest in the mushrooms used, and which were likely most beneficial in treatment. The mechanism of action for lowering the PSA in this study is unknown.
 
Mushrooms tend to readily absorb both nutrients and toxic elements from their growth media. Therefore being aware of any toxic elements in the growth media is critical. The supplemental materials showed a very thorough analysis of potential toxins, including arsenic, lead, and cadmium, as well as some biological contaminants like E. coli and Salmonella, all of which were negative.

About the Author

Sara Thyr, ND, graduated from Bastyr University’s naturopathic medicine and midwifery programs. While practicing in New Hampshire, she was the president of the New Hampshire Association of Naturopathic Physicians and was subsequently appointed by then Governor Lynch to the New Hampshire Board of Naturopathic Examiners. She has served 2 terms on the board of directors for the American Association of Naturopathic Physicians (AANP), chairing the convention committee during this time. Thyr has been a popular public lecturer, providing continuing education lectures to naturopathic physicians as well as medical doctors, midwives, and nurse practitioners. In 2008 Thyr moved to Petaluma, Calif., where she founded Willowbend Natural Medicine. She lives in Petaluma with her husband and two cats and is an avid gardener, swimmer, tennis player, and a budding permaculturist and mushroom forager.

References

  1. Twardowski P, Kanaya N, Frankel P, et al. A phase I trial of mushroom powder in patients with biochemically recurrent prostate cancer: Roles of cytokines and myeloid-derived suppressor cells for Agaricus bisporus-induced prostate-specific antigen responses. Cancer. 2015;121(17):2942-2950. 
  2. Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006;24(27):4448-4456.
  3. 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. 2006;12(13):4018-4026.
  4. Guess BW, Scholz MC, Strum SB, Lam RY, Johnson HJ, Jennrich RI. 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. 2003;6(4):301-304.
  5. Vaishampayan U, Hussain M, Banerjee M, et al. Lycopene and soy isoflavones in the treatment of prostate cancer. Nutr Cancer. 2007;59(1):1-7.
  6. Xu T, Beelman RB, Lambert JD. The cancer preventive effects of edible mushrooms. Anticancer Agents Med Chem. 2012;12(10):1255-1263.
  7. Eliza WL, Fai CK, Chung LP. Efficacy of Yun Zhi (Coriolus versicolor) on survival in cancer patients: systematic review and meta-analysis. Recent Pat Inflamm Allergy Drug Discov. 2012 6(1):78-87.
  8. Grube BJ, Eng ET, Kao YC, Kwon A, Chen S. White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation. J Nutr. 2001;131(12):3288-3293.
  9. Chen S, Oh SR, Phung S, et al. Anti-aromatase activity of phytochemicals in white button mushrooms (Agaricus bisporus). Cancer Res. 2006;66(24):12026-12034.
  10. Yu L, Fernig DG, Smith JA, Milton JD, Rhodes JM. Reversible inhibition of proliferation of epithelial cell lines by Agaricus bisporus (edible mushroom) lectin. Cancer Res. 1993;53(19):4627-4632.
  11. Kanaya N, Kubo M, Liu Z, Chu P, Wang C, Yuan YC, Chen S. Protective effects of white button mushroom (Agaricus bisporus) against hepatic steatosis in ovariectomized mice as a model of postmenopausal women. PLoS One. 2011;6(10):e26654.