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PC-SPES (PDQ®): Complementary and alternative medicine - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

PC-SPES

Overview

This complementary and alternative medicine (CAM) information summary provides an overview of the use of PC-SPES as a treatment in people with cancer. The summary includes a brief history of PC-SPES research, the results of clinical trials, and possible adverse effects of PC-SPES. Included in this summary is a discussion of the contamination of PC-SPES and its withdrawal from avenues of distribution.

This summary contains the following key information:

  • PC-SPES is a patented mixture of eight herbs.
  • PC-SPES was sold as a dietary supplement to support and promote healthy prostate function.
  • Each herb used in PC-SPES has been reported to have anti-inflammatory, antioxidant, or anticarcinogenic properties.
  • PC-SPES was recalled and withdrawn from the market because certain batches were contaminated with Food and Drug Administration–controlled prescription drugs.
  • The manufacturer is no longer in operation, and PC-SPES is no longer being made.
  • There is evidence from both laboratory and animal studies to suggest that PC-SPES had some effect in inhibiting prostate cancer cell growth and prostate-specific antigen (PSA) expression, but it is not known whether these results were caused by adulterants such as diethylstilbestrol, which is an estrogenic compound, the herbs in PC-SPES, or their combination.
  • Evidence from clinical trials has shown that PC-SPES lowers PSA and testosterone levels in humans, but it is not known whether these results were caused by adulterants, the herbs in PC-SPES, or their combination.
  • There is some evidence to suggest that PC-SPES has some anticancer effects that are not related to estrogen-like activity.
  • Although there are products that claim to be substitutes for PC-SPES, they are not the patented original formulation. Few of these products have been the subject of laboratory or clinical trials reported in the peer-reviewed medical literature.

General Information

Note: A separate PDQ summary on Prostate Cancer Treatment is also available.

PC-SPES is a patented herbal mixture that was sold as a dietary supplement and used as a complementary and alternative medicine (CAM) treatment for prostate cancer. It is a combination of the following eight herbs:

  • Baikal skullcap (Scutellaria baicalensis Georgi).
  • Chrysanthemum (Dendranthema morifolium [Ramat.] Tzvelev [synonym Chrysanthemum morifolium]).
  • Ganoderma (Ganoderma lucidum [Curtis:fr] Karst.).
  • Isatis (Isatis indigotica Fort.).
  • Licorice (Glycyrrhiza glabra L. or Glycyrrhiza uralensis Fisch. ex DC.).
  • Panax ginseng C.A. Meyer or pseudoginseng (Panax pseudoginseng var. notoginseng Hoo & tseng [synonym Panax notoginseng (Burkill)] F.H.Chen).
  • Isodon rubescens (Hemsl.) Hara (synonym Rabdosia rubescens [Hemsl.] Hara).
  • Saw palmetto (Serenoa repens [Bartr.] Small).

With the exception of saw palmetto, the herbs in PC-SPES have been used individually or in combination in Traditional Chinese Medicine (TCM) for a variety of health problems, including those of the prostate, for hundreds of years.[1,2]

PC-SPES is an herbal product that resulted from a collaboration between a chemist at the New York Medical College in Valhalla, New York, and a Chinese herbalist and doctor of TCM in China. Their idea was to combine TCM with the scientific techniques of Western laboratory research. In the United States, a series of in vitro and in vivo laboratory studies was started on the mixture of herbs used in TCM specially formulated to treat prostate problems. Researchers published the results of these studies, which showed promising anticancer activity from PC-SPES.[3,4,5,6,7,8,9,10,11]

Considerable research has been conducted on the anticancer properties of the eight individual botanicals in PC-SPES.

Baikal skullcap (Scutellaria baicalensis)—Chinese name huang qin—contains baicalin and wogonin, two active flavones. Baicalin converts to baicalein, which is another active flavone. In vitro, baicalin and baicalein inhibit cell growth of AD LNCaP and JCA-1 AI human prostate cancer cell lines,[12,13] as well as inducing apoptosis in human LNCaP cells.[14] Baicalin also shows antimutagenic and antioxidant activity in vitro as well as free radical scavenging ability.[15,16,17,18,19,20]

Licorice (Glycyrrhiza glabra or Glycyrrhiza uralensis)—Chinese name gan cao—contains the very active flavonoid licochalcone A, which has demonstrated in vitro estrogenic activity.[21] This botanical shows a broad range of anticancer activity in vitro. It enhances the cytotoxicity of commonly used anticancer drugs and induces apoptosis in MCF-7 human breast cancer and HL-60 promyelocytic leukemia cell lines.[21,22,23,24]

Reishi mushroom (Ganoderma lucidum [Curtis: fr.] Karst.)—Chinese name ling zhi— has been shown to aid in the recovery of leukocyte counts in irradiated mice in a dose-dependent manner. It contains the polysaccharide G009, which has demonstrated antioxidant behavior against HL-60 cells in vitro and dose-dependent inhibition of lipid peroxidation in rat brain cells in vitro.[25,26,27,28,29]

Isatis (Isatis indigotica)—Chinese name da qing ve—contains active agents in each part of the plant.[2] TCM has different names for the medicinals coming from the leaf, stem, and root and uses these plant products for different purposes. Indirubin, an active ingredient, and its analogs have demonstrated inhibition of cyclin-dependent kinases in human mammary carcinoma cell line MCF-7 in vitro.[30]

Ginseng (Panax ginseng or Panax pseudoginseng var. notoginseng)—Chinese name tianqi—contains ginsenosides and saponins. Of the 30 ginsenosides that have been isolated from Panax ginseng, only the 20(S)-protopanaxadiol type R3 has inhibited cell growth and suppressed PSA expression, androgen receptor and 5-alpha-reductase activity, and PCNA production in vitro.[31,32,33]

Chrysanthemum flowers (Dendranthema morifolium)—Chinese name ju hua—contain triterpene diols and triols. Arnidiol exhibited cytotoxicity in vitro against 58 of the 60 human cancer cell lines developed by the National Cancer Institute (NCI) Developmental Therapeutics Program.[34]

The botanical rabdosia rubescens (Isodon rubescens)—Chinese name dong ling cao—has two very active agents, oridonin and rubesencin b. Oridonin inhibits DNA synthesis in vitro Reviewed in [1], and rubesencin b inhibited cell growth in cancer cell lines in vitro and in a mouse model.[35]

Saw palmetto (Serenoa repens) is the only botanical in PC-SPES that is not used in TCM. There is strong evidence from human trials that saw palmetto has some activity against benign prostatic hypertrophy (BPH), including improved urine flow and less erectile dysfunction when compared with placebo or finasteride. S. repens also exhibits antiestrogenic activity in placebo-controlled BPH trials. In LNCaP cells, S. repens produced apoptosis in vitro.[36,37,38,39,40]

Exactly how PC-SPES works in the body is still unknown. The presence of adulterants and varying amounts of the active agents in each lot of PC-SPES complicates the interpretation of any results from studies that might lead to an explanation of its mechanisms of action. More studies of the individual components of the mixture and testing of a standard formulation that is free of adulterants are needed before any conclusions can be reached about the level of cytotoxicity, antineoplasticity, or estrogenicity of PC-SPES.

The National Center for Complementary and Alternative Medicine (NCCAM) stopped funding to studies of PC-SPES after the drug contamination was detected and made public, although the laboratory studies were later resumed.

Although manufacturers are selling supplements purporting to be substitutes, the only company that had a license from the patent holder to manufacture PC-SPES is no longer in business, and the product cannot be legally manufactured in the United States without the patent holder's permission. PC-SPES is not legally available in the United States.

References:

1. Huang KC, Williams WM: The Pharmacology of Chinese Herbs. 2nd ed. Boca Raton, Fl: CRC Press, 1998.
2. Zhu YP: Chinese Materia Medica: Chemistry, Pharmacology, and Applications. Amsterdam, The Netherlands: Harwood Academic, 1998.
3. Halicka HD, Ardelt B, Juan G, et al.: Apoptosis and cell cycle effects induced by extracts of the Chinese herbal preparation PC SPES. Int J Oncol 11: 437-48, 1997.
4. Hsieh T, Chen SS, Wang X, et al.: Regulation of androgen receptor (AR) and prostate specific antigen (PSA) expression in the androgen-responsive human prostate LNCaP cells by ethanolic extracts of the Chinese herbal preparation, PC-SPES. Biochem Mol Biol Int 42 (3): 535-44, 1997.
5. Chenn S: In vitro mechanism of PC SPES. Urology 58 (2 Suppl 1): 28-35; discussion 38, 2001.
6. Hsieh TC, Wu JM: Mechanism of action of herbal supplement PC-SPES: elucidation of effects of individual herbs of PC-SPES on proliferation and prostate specific gene expression in androgen-dependent LNCaP cells. Int J Oncol 20 (3): 583-8, 2002.
7. Chen S, Ruan Q, Bedner E, et al.: Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines. Cell Prolif 34 (5): 293-304, 2001.
8. Kubota T, Hisatake J, Hisatake Y, et al.: PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo . Prostate 42 (3): 163-71, 2000.
9. Darzynkiewicz Z, Traganos F, Wu JM, et al.: Chinese herbal mixture PC SPES in treatment of prostate cancer (review). Int J Oncol 17 (4): 729-36, 2000.
10. Marks LS, DiPaola RS, Nelson P, et al.: PC-SPES: herbal formulation for prostate cancer. Urology 60 (3): 369-75; discussion 376-7, 2002.
11. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001.
12. Huerta S, Arteaga JR, Irwin RW, et al.: PC-SPES inhibits colon cancer growth in vitro and in vivo. Cancer Res 62 (18): 5204-9, 2002.
13. Schwarz RE, Donohue CA, Sadava D, et al.: Pancreatic cancer in vitro toxicity mediated by Chinese herbs SPES and PC-SPES: implications for monotherapy and combination treatment. Cancer Lett 189 (1): 59-68, 2003.
14. Chan FL, Choi HL, Chen ZY, et al.: Induction of apoptosis in prostate cancer cell lines by a flavonoid, baicalin. Cancer Lett 160 (2): 219-28, 2000.
15. Okita K, Li Q, Murakamio T, et al.: Anti-growth effects with components of Sho-saiko-to (TJ-9) on cultured human hepatoma cells. Eur J Cancer Prev 2 (2): 169-75, 1993.
16. Matsuzaki Y, Kurokawa N, Terai S, et al.: Cell death induced by baicalein in human hepatocellular carcinoma cell lines. Jpn J Cancer Res 87 (2): 170-7, 1996.
17. Kimura Y, Matsushita N, Okuda H: Effects of baicalein isolated from Scutellaria baicalensis on interleukin 1 beta- and tumor necrosis factor alpha-induced adhesion molecule expression in cultured human umbilical vein endothelial cells. J Ethnopharmacol 57 (1): 63-7, 1997.
18. Hsieh TC, Lu X, Chea J, et al.: Prevention and management of prostate cancer using PC-SPES: a scientific perspective. J Nutr 132 (11 Suppl): 3513S-3517S, 2002.
19. Ikezoe T, Chen SS, Heber D, et al.: Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest. Prostate 49 (4): 285-92, 2001.
20. Hsu SL, Hsieh YC, Hsieh WC, et al.: Baicalein induces a dual growth arrest by modulating multiple cell cycle regulatory molecules. Eur J Pharmacol 425 (3): 165-71, 2001.
21. Gao Z, Huang K, Yang X, et al.: Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi. Biochim Biophys Acta 1472 (3): 643-50, 1999.
22. Armanini D, Bonanni G, Palermo M: Reduction of serum testosterone in men by licorice. N Engl J Med 341 (15): 1158, 1999.
23. Rafi MM, Vastano BC, Zhu N, et al.: Novel polyphenol molecule isolated from licorice root (Glycrrhiza glabra) induces apoptosis, G2/M cell cycle arrest, and Bcl-2 phosphorylation in tumor cell lines. J Agric Food Chem 50 (4): 677-84, 2002.
24. Rafi MM, Rosen RT, Vassil A, et al.: Modulation of bcl-2 and cytotoxicity by licochalcone-A, a novel estrogenic flavonoid. Anticancer Res 20 (4): 2653-8, 2000 Jul-Aug.
25. Wang ZY, Nixon DW: Licorice and cancer. Nutr Cancer 39 (1): 1-11, 2001.
26. Bao XF, Wang XS, Dong Q, et al.: Structural features of immunologically active polysaccharides from Ganoderma lucidum. Phytochemistry 59 (2): 175-81, 2002.
27. Chen WC, Hau DM, Lee SS: Effects of Ganoderma lucidum and krestin on cellular immunocompetence in gamma-ray-irradiated mice. Am J Chin Med 23 (1): 71-80, 1995.
28. Hsu HY, Lian SL, Lin CC: Radioprotective effect of Ganoderma lucidum (Leyss. ex. Fr.) Karst after X-ray irradiation in mice. Am J Chin Med 18 (1-2): 61-9, 1990.
29. Lee JM, Kwon H, Jeong H, et al.: Inhibition of lipid peroxidation and oxidative DNA damage by Ganoderma lucidum. Phytother Res 15 (3): 245-9, 2001.
30. Marko D, Schätzle S, Friedel A, et al.: Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer 84 (2): 283-9, 2001.
31. Liu WK, Xu SX, Che CT: Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci 67 (11): 1297-306, 2000.
32. Yun TK, Lee YS, Lee YH, et al.: Anticarcinogenic effect of Panax ginseng C.A. Meyer and identification of active compounds. J Korean Med Sci 16 (Suppl): S6-18, 2001.
33. Surh YJ, Na HK, Lee JY, et al.: Molecular mechanisms underlying anti-tumor promoting activities of heat-processed Panax ginseng C.A. Meyer. J Korean Med Sci 16 (Suppl): S38-41, 2001.
34. Ukiya M, Akihisa T, Tokuda H, et al.: Constituents of Compositae plants III. Anti-tumor promoting effects and cytotoxic activity against human cancer cell lines of triterpene diols and triols from edible chrysanthemum flowers. Cancer Lett 177 (1): 7-12, 2002.
35. Jing JY, Reed E: Preliminary study of the effect of selected Chinese natural drugs on human ovarian cancer cells. Oncol Rep 2: 571-5, 1995.
36. Marks LS, Hess DL, Dorey FJ, et al.: Tissue effects of saw palmetto and finasteride: use of biopsy cores for in situ quantification of prostatic androgens. Urology 57 (5): 999-1005, 2001.
37. Di Silverio F, D'Eramo G, Lubrano C, et al.: Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. Eur Urol 21 (4): 309-14, 1992.
38. Di Silverio F, Monti S, Sciarra A, et al.: Effects of long-term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia. Prostate 37 (2): 77-83, 1998.
39. Iguchi K, Okumura N, Usui S, et al.: Myristoleic acid, a cytotoxic component in the extract from Serenoa repens, induces apoptosis and necrosis in human prostatic LNCaP cells. Prostate 47 (1): 59-65, 2001.
40. Wilt T, Ishani A, Mac Donald R: Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev (3): CD001423, 2002.

History

In 1997, the herbal formula for PC-SPES was patented in the United States.[1] A company, BotanicLab (Brea, California), was formed to produce, distribute, and sell the product. PC-SPES was sold through the BotanicLab Web site (the Web site was taken down after PC-SPES was recalled) and through selected distributors. Anecdotal information about the product and its positive effects was widely circulated on the Internet through Web sites that informed prostate cancer patients about new developments in treatment. At the same time, the published papers were being read by the scientific community, and the findings were presented at various conferences. As a result, clinicians and researchers began looking at PC-SPES as one of the first viable treatments to come out of the alternative medicine community.

The manufacturing process for PC-SPES has been described by the manufacturer as follows: extracts of raw plant material were obtained from the specified plants, which were grown in particular geographic regions in China and harvested at certain times of the year to reduce the natural variation inherent in any biological product. The extracts were shipped to the United States, where high-performance liquid chromatography (HPLC) was used to monitor the key active compounds—which are believed to be directly related to the clinical effects—for batch-to-batch reproducibility. Activity-related biomarkers were kept in a constant concentration from lot to lot. A commercial testing laboratory (Truesdail Laboratory; Tustin, California) was used to guarantee that each batch was free from contamination with heavy metals, pesticides, microorganisms and products, and prescription drugs. Each lot was standardized by an anticancer bioassay for an effective dose of 50% in vitro inhibition of cell growth using human LNCaP cells for androgen-dependent (AD) prostate cancer and DU-145 cells for androgen-independent (AI) prostate cancer. The powder was then encapsulated, bottled, labeled, and sterilized at the BotanicLab facility.[2]

In 2001, allegations that PC-SPES contained the synthetic estrogen diethylstilbestrol (DES) started to appear on e-mail listservs used by prostate cancer patients and in online newsletters. Prostate cancer patients who were taking PC-SPES noticed that their recent medication was not as effective as the previous batches.[3] A sample of PC-SPES submitted to a testing laboratory by BotanicLab in August 2001 found no DES. BotanicLab posted the letter from the laboratory on their Web site, claiming that PC-SPES contained no DES. However, in other tests of six different lots of PC-SPES received from two different sources in August 2001, Rocky Mountain Instrumental Laboratory found varying amounts of DES in three lots. More tests done by the California Department of Health Services in February 2002 did not find DES but did find warfarin, a prescription drug used as a blood thinner.[4]

The presence of a synthetic estrogen such as DES was suspected early in the clinical use of PC-SPES after reports in the literature discussed the mixture's estrogen-like ability to lower prostate-specific antigen (PSA) levels in AD prostate cancer patients. In addition, the side effects of treatment were similar to those of estrogen therapy. [5,6,7] In one study, patients who showed the most response to PC-SPES were also those who were the most responsive to DES. Reviewed in [8,9] The same study also attempted to find out whether DES or similar compounds were present in PC-SPES. Transcriptional activation assays in yeast strain PL3 Saccharomyces cerevisiae using an ethanolic extract of PC-SPES showed estrogenic activity similar to 1nM estradiol. In addition, ovariectomized CD-1 mice showed substantially increased uterine weights. HPLC, gas chromatography, and mass spectrometry did not reveal the presence of DES but rather that of a compound with similar chemical characteristics. The authors of the report concluded that PC-SPES contains estrogenic compounds that are distinct from DES or other synthetic estrogens.[9]

A definitive evaluation of PC-SPES analyzed specific lots of PC-SPES capsules manufactured from 1996 to 2001.[10] In addition to using HPLC to isolate, identify, and quantify the synthetic drugs and active phytoestrogens, this study also identified components using proton nuclear magnetic resonance, gas chromatography/mass spectrometry, and mass spectra analysis. Tests showed the presence of the synthetic drugs indomethacin (a nonsteroidal anti-inflammatory drug not previously reported in the literature or found in other testing), DES, and warfarin. Testing was also done for concentrations of the two naturally occurring phytosterols, licochalcone A and baicalin. Test results indicated a history of rising and falling levels of contamination by the three synthetic drugs and a recent rise in the naturally occurring phytochemicals in PC-SPES. Lots of PC-SPES manufactured in 1996 through mid-1999 contained indomethacin ranging from 1.07 mg/g to 13.19 mg/g and DES ranging from 107.28 µg/g to 159.27 µg/g and were 2 to 6 times more antineoplastic and up to 50 times more estrogenic than lots manufactured after the spring of 1999. In vitro testing of ethanolic extracts of PC-SPES against LNCaP, PC-3, and DU-145 prostate cancer cell lines showed a decrease in both antineoplasticity and estrogenicity in lots of PC-SPES manufactured in June 1998 through August 2001, which correlated with the amount of DES and indomethacin contamination.[10] Another in vitro test of suspected lots of PC-SPES manufactured from 2000 to 2001 also showed the presence of DES.[11]

Although the laboratory testing showed that certain lots of the mixture contained indomethacin, warfarin, and DES, the amount of DES present may not have accounted for all of the estrogenic effect of PC-SPES. There is some evidence that the mixture acts differently from DES at the molecular level.[12,13] In addition, its anticancer effects on both AI prostate cancer and AD prostate cancer may point to a mechanism other than estrogen-like activity.[10,14,15] The in vitro activity of PC-SPES against cancer cells other than prostate also gives rise to the speculation that its estrogen-like qualities might not account for all of the mixture's anticancer activity.[16,17]

References:

1. Chen S, Wang X: Herbal Composition for Treating Prostate Carcinoma. US Patent 5665393. September 9, 1997. Washington, DC: US Patent and Trademark Office, 1997. Available online. Last accessed August 7, 2013.
2. Marks LS, DiPaola RS, Nelson P, et al.: PC-SPES: herbal formulation for prostate cancer. Urology 60 (3): 369-75; discussion 376-7, 2002.
3. PSA Rising: Prostate Cancer Survivor News, Info and Support. New York, NY: PSA Rising, 2005. Available online. Last accessed August 7, 2013.
4. Ko R, Wilson RD, Loscutoff S: PC-SPES. Urology 61 (6): 1292, 2003.
5. Oh WK, George DJ, Hackmann K, et al.: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 57 (1): 122-6, 2001.
6. Oh WK, George DJ, Kantoff PW: Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma: report of four cases. Cancer 94 (3): 686-9, 2002.
7. de la Taille A, Hayek OR, Burchardt M, et al.: Role of herbal compounds (PC-SPES) in hormone-refractory prostate cancer: two case reports. J Altern Complement Med 6 (5): 449-51, 2000.
8. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001.
9. DiPaola RS, Zhang H, Lambert GH, et al.: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339 (12): 785-91, 1998.
10. Sovak M, Seligson AL, Konas M, et al.: Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 94 (17): 1275-81, 2002.
11. Guns ES, Goldenberg SL, Brown PN: Mass spectral analysis of PC-SPES confirms the presence of diethylstilbestrol. Can J Urol 9 (6): 1684-8; discussion 1689, 2002.
12. Chen S, Ruan Q, Bedner E, et al.: Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines. Cell Prolif 34 (5): 293-304, 2001.
13. Bonham M, Arnold H, Montgomery B, et al.: Molecular effects of the herbal compound PC-SPES: identification of activity pathways in prostate carcinoma. Cancer Res 62 (14): 3920-4, 2002.
14. Reynolds T: Contamination of PC-SPES remains a mystery. J Natl Cancer Inst 94 (17): 1266-8, 2002.
15. Malkowicz SB: The role of diethylstilbestrol in the treatment of prostate cancer. Urology 58 (2 Suppl 1): 108-13, 2001.
16. Huerta S, Arteaga JR, Irwin RW, et al.: PC-SPES inhibits colon cancer growth in vitro and in vivo. Cancer Res 62 (18): 5204-9, 2002.
17. Schwarz RE, Donohue CA, Sadava D, et al.: Pancreatic cancer in vitro toxicity mediated by Chinese herbs SPES and PC-SPES: implications for monotherapy and combination treatment. Cancer Lett 189 (1): 59-68, 2003.

Laboratory / Animal / Preclinical Studies

Before the discovery of diethylstilbestrol (DES), warfarin, and indomethacin contamination, PC-SPES appeared to have some efficacy as an antineoplastic agent in laboratory and animal studies. These studies are presented below. Due to the fact that there was no standardization of the composition of PC-SPES or any knowledge of the amount of contamination of each lot used in testing, it is difficult to interpret the data from these studies.

In one study that attempted to measure the effects of the whole PC-SPES mixture versus that of individual herbs of PC-SPES on prostate-specific antigen (PSA) expression and cell growth, LNCaP cells were treated with ethanol extracts of PC-SPES and each of the eight herbs. The PC-SPES mixture reduced cell growth by 72% to 80%, while Dendranthema morifolium (Ramat.) Tzvelev (synonym Chrysanthemum morifolium) (chrysanthemum) produced the highest reduction of the herb group at 85%. Panax pseudoginseng var. notoginseng Hoo & tseng (Synonym Panax notoginseng [Burkill] F.H.Chen) was next at 80.9% reduction, followed by Glycyrrhiza uralensis Fisch ex DC. (73%). The lowest reduction in cell growth was exhibited by Serenoa repens (Bartr.) Small (14.5%). Scutellaria baicalensis Georgi, Serenoa repens, and Glycyrrhiza uralensis lowered PSA expression, but each of the other herbs increased PSA expression. The ability of individual herbs to reduce PSA expression was not uniform, but the PC-SPES mixture as a whole exhibited a uniform response. The varying results with the individual herbs and the positive response of the cells (i.e., increased cytotoxicity and reduced PSA expression) to the aggregate PC-SPES mixture may suggest that the botanicals in PC-SPES work in concert and that no individual herb can account for the overall effects of the mixture.[1]

In other studies, PC-SPES was found to inhibit clonal growth in three human prostate cancer cell lines: LNCaP, PC-3, and DU-145. Cell cycle analysis showed cell cycle arrest at the G2 phase.[2]Cell proliferation and reduced clonogenicity were observed in cancer cell lines other than those of prostate cancer: human breast carcinoma lines MCF-7 and T47-D, SK-N-MC neuroepithelioma, COLO 38 melanoma, U937 histiomonocytic lymphoma, and HL-60 and MOLT-4 leukemias. Cytotoxic and cytostatic effects of PC-SPES were common to all tumor cell lines tested.[3]

In another study evaluating regulation of PSA expression and androgen receptor (AR) activity, LNCaP prostate cancer cell lines showed downregulation of both proliferating cell nuclear antigen (PCNA) and PSA expression. PSA changes occurred concurrently with the decrease of PCNA. The results suggest that PC-SPES modulates cell growth by changing PCNA expression and may decrease PSA levels indirectly by suppressing AR expression.[4]

None of the studies above indicated lot number or year of manufacture of the PC-SPES used. Therefore, it is not possible to assess the amount of contamination of the mixtures used in the studies or whether the mixtures used were not in fact contaminated.

A 1998 study that evaluated estrogenic activity of extracts of PC-SPES, ginseng (Panax ginseng C.A. Meyer), saw palmetto, DES, and estrone (estradiol -17 beta) in vitro reported on the estrogenic response of ovariectomized CD-1 mice to PC-SPES extract as well as the response to PC-SPES capsules in eight prostate cancer patients who had received previous therapy. [5] This study used four samples of PC-SPES ordered in separate purchases from BotanicLab. No lot numbers were supplied in the study. Lot numbers from October 1996 through July 1998 were later tested for contamination and had DES levels of 114.74 μg/g to 159.27 μg/g, as well as the highest detected levels of indomethacin of the PC-SPES lots tested.[6]In vitro tests of PC-SPES extract or estradiol showed estrogenic activity similar to 1 nM estradiol on estrogen receptor Y253 yeast strain. Transcriptional activation assays in yeast strain PL3 Saccharomyces cerevisiae with ethanolic extract of PC-SPES exhibited estrogen-like effects. In the eight prostate cancer patients, serum testosterone concentrations decreased during the use of PC-SPES and increased within 3 weeks after treatment was discontinued. PSA levels decreased in all eight patients. Side effects in all eight patients were similar to those seen after treatment with estrogen: breast tenderness and loss of libido. One patient had superficial venous thrombosis. In addition to baicalin, two other compounds purified from PC-SPES, isoliquiritigenin and wogonin, have been shown to reduce PSA levels and downregulate AR.[7]

By incorporating PC-SPES into the rat diet, researchers conducting an in vivo study showed antitumor effects using a Dunning R3327 rat prostate cancer model. Levels of 0.05% and 0.025% of dietary PC-SPES were fed to the rats over a 6-week period. No toxicity was seen, nor was there a difference in the food intake of the rats during this time. Pulmonary tumors were induced by intradermal injections of MAT-LyLu cells, which are particularly resistant to many forms of treatment. Tumor incidence was inhibited in a dose-dependent manner, and the rate of tumor growth showed the same dose-dependent response.[8,9]

In another study, which used male BNX nu/nu immunodeficient nude mice, PC-SPES was also administered orally, but in suspension. The mice received 300 rad of whole-body irradiation, after which they were inoculated with either PC-3 or DU-145 prostate cancer cell lines. Treatment with PC-SPES began the day after injection. Results showed that PC-SPES suppressed the growth of DU-145 tumors compared with tumor growth in the control group. Cytological analysis showed apoptosis in the treated group that was not apparent in the control group.[10]

In two other studies, clinical studies of patients were initiated along with in vitro and in vivo research. The results of these two patient groups are discussed in the Human/Clinical Trials section of this summary. The first study, preceding more extensive research, examined in vitro activity of PC-SPES against LNCaP, LNCaP-bcl-2, PC-3, and DU-145 cells lines. Results showed that PC-SPES was active in suppressing both hormone -sensitive and hormone-insensitive prostate cancer cell lines. In the subsequent study, research was conducted in vitro on the ability of PC-SPES to induce apoptosis in androgen-independent (AI) prostate cancer cell lines, and in vivo on the effect of oral PC-SPES on the growth of xenografted PC-3 tumors in immunodeficient male mice. Mice in the treatment arm—in which treatment was started 1 week after implantation—showed a significant decrease in tumor weight when compared with mice in the control arm. PC-SPES showed activity against both androgen -sensitive and AI prostate cancer in the patients and suppressed tumor growth in AI tumors in mice. Reviewed in [10,11,12] In both studies, the patients were given capsules manufactured between 1996 and 1999, a time when contamination levels of DES were highest.[6]

Another study in rats demonstrated that PC-SPES (one lot contaminated with DES and one lot without DES) caused some decrease in the activity of a liver enzyme involved in drug metabolism (CYP3A).[13]

References:

1. Hsieh TC, Lu X, Chea J, et al.: Prevention and management of prostate cancer using PC-SPES: a scientific perspective. J Nutr 132 (11 Suppl): 3513S-3517S, 2002.
2. Kubota T, Hisatake J, Hisatake Y, et al.: PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo . Prostate 42 (3): 163-71, 2000.
3. Ko R, Wilson RD, Loscutoff S: PC-SPES. Urology 61 (6): 1292, 2003.
4. Hsieh TC, Wu JM: Mechanism of action of herbal supplement PC-SPES: elucidation of effects of individual herbs of PC-SPES on proliferation and prostate specific gene expression in androgen-dependent LNCaP cells. Int J Oncol 20 (3): 583-8, 2002.
5. DiPaola RS, Zhang H, Lambert GH, et al.: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339 (12): 785-91, 1998.
6. Sovak M, Seligson AL, Konas M, et al.: Herbal composition PC-SPES for management of prostate cancer: identification of active principles. J Natl Cancer Inst 94 (17): 1275-81, 2002.
7. Chen S, Gao J, Halicka HD, et al.: Down-regulation of androgen-receptor and PSA by phytochemicals. Int J Oncol 32 (2): 405-11, 2008.
8. Tiwari RK, Geliebter J, Garikapaty VP, et al.: Anti-tumor effects of PC-SPES, an herbal formulation in prostate cancer. Int J Oncol 14 (4): 713-9, 1999.
9. Geliebter J, Mittelman A, Tiwari RK: PC-SPES and prostate cancer. J Nutr 131 (1): 164S-166S, 2001.
10. de la Taille A, Buttyan R, Hayek O, et al.: Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 164 (4): 1229-34, 2000.
11. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001.
12. de la Taille A, Hayek OR, Buttyan R, et al.: Effects of a phytotherapeutic agent, PC-SPES, on prostate cancer: a preliminary investigation on human cell lines and patients. BJU Int 84 (7): 845-50, 1999.
13. Wadsworth T, Poonyagariyagorn H, Sullivan E, et al.: In vivo effect of PC-SPES on prostate growth and hepatic CYP3A expression in rats. J Pharmacol Exp Ther 306 (1): 187-94, 2003.

Human / Clinical Studies

One published randomized cross-over study of patients with androgen-independent (AI) prostate cancer who initially received either 960 mg of PC-SPES 3 times a day or 3 mg of diethylstilbestrol (DES) once a day before crossing over to the other regimen; when disease progression occurred, there were reports of data demonstrating the presence and levels of adulterants in the four lots of PC-SPES used in this trial. The lots were manufactured by BotanicLab (Brea, California). The study was halted and chemical analyses of the lots were performed. The analyses showed that all four lots of PC-SPES contained amounts of DES ranging from 0.1 μg/g to 32.7μg/g, and that one lot contained varying amounts of ethinyl estradiol. The authors concluded that the presence of these adulterants rendered their results inconclusive.[1]

Several nonrandomized clinical studies published between 1999 and 2003 described the results of clinical trials conducted before adulterants had been conclusively identified in PC-SPES lots and before it was known that there was significant variation in naturally occurring active agents, such as baicalein and licochalcone-A, in the lots. These studies, many of which enrolled small numbers of patients, did not identify the source of the lots that were used in the trials, nor did they identify where patients acquired PC-SPES.

In addition to the confounding effects of adulterants on the clinical trial results discussed below, the fact that an optimal dose of PC-SPES remains undetermined and that dose varies among these studies makes it difficult to compare their findings.

In a retrospective study of 23 consecutive patients with AI disease, charts were evaluated for patients' responses to PC-SPES and the occurrence of any toxicity. There is no report of where the patients acquired their PC-SPES or what lots were used. Patients were all seen between February and November in 1999. Patients ranged in age from 51 to 88 years, with a median age of 70 years. All had previous initial androgen ablation for a period of 6 months to 144 months. Ten patients had received chemotherapy, 13 had not. More than half of the patients with AI showed a post-therapy prostate-specific antigen (PSA) decline of 50% or greater. Median time to PSA progression was 6 months. The side effects were similar to those of estrogen therapy (gynecomastia and impotence). Other side effects were nausea/vomiting and diarrhea and to a lesser extent, allergic reactions, leg cramps, and leg swelling.[2]

In a prospective clinical trial of 16 men with stage D3 metastatic prostate cancer in which all patients had failed therapy and had disease progression, the effects of PC-SPES on pain, quality of life, and side effects were assessed. Previous therapy was either orchidectomy or a luteinizing hormone–releasing agonist with or without antiandrogen. Hormonal therapy was continued throughout the trial to avoid the known withdrawal effect of antiandrogen on PSA levels. There was a significant decrease in pain scores such that the 14 patients on analgesics required an average of 40% less analgesics while taking PC-SPES. PC-SPES treatment was associated with improved function and emotional and physical well-being. PSA levels declined significantly after PC-SPES therapy (>50%). Side effects were breast tenderness, deep venous thrombosis, and mild dyspepsia. Reviewed in [3,4]

In a study of 70 patients, 37 with androgen -dependent (AD) disease and 33 with AI disease, the AD cohort was treated with PC-SPES only after an initial treatment with prostatectomy, radiation, cryotherapy, and/or hormonal therapy. Median duration of PSA response was greater than 57 weeks. All patients in the AD cohort had PSA declines within a range of 80% to 100%, and two patients with bone metastases showed improvement on radiographic analysis. Within the AI cohort, 54% (19 of 35) had a PSA decrease of greater than 50%, with median time to nadir of 10 weeks and a median duration of 18 weeks. Eight of the 16 patients who had received ketoconazole therapy prior to PC-SPES also obtained a decrease of greater than 50% in their PSA values. Testosterone levels within the AD group decreased to castrate levels (<50 ng/mL) in 94% of patients (31 of 33), and libido (25 of 25) and potency (15 of 15) were lost in all patients who entered the study. Side effects were hot flashes, gynecomastia/gynecodynia, and thromboembolic effects in 3 of 70 patients. Although the results of this trial were promising for the treatment of both AI and AD prostate cancer, it is not possible to assess what was responsible for these effects. This trial used PC-SPES from one single lot, but the published study does not indicate the lot number. The research was completed before 2000. No attempt was made to assess the possible contamination of the product. Reviewed in [3,5]

A prospective clinical series assessed the ability of PC-SPES to lower serum PSA levels in 33 prostate cancer patients. The patients had either refused conventional therapy or had failed previous cryosurgery, radiation therapy, and/or hormonal therapy. No overt signs of disease progression were found in any of the patients. At 2 months, PSA levels had decreased by a mean of 52% in 27 of the 31 patients and had increased in two patients. Of the five patients who had hormone -refractory disease, all had decreased serum PSA levels. Reviewed in [3,6]

In a continuation of the previous study, a total of 69 patients with either AI or AD disease were separated into three study groups. Group one (n = 43) had undergone previous therapy, including hormonal; group two (n = 22) developed AI after treatment; and group three (n = 4) had not undergone previous therapy. The study assessed PC-SPES activity in suppressing PSA levels. Patients were given three capsules of PC-SPES 3 times per day. PSA levels and side effects were observed for 24 months.[7]

In group one, 82% of patients (32 of 39) had a decrease in PSA levels, with 20 patients having a decrease of greater than 50% at 2 months' follow-up; the decrease lasted for 24 months in two patients. In group two (AI patients), 90% (19 of 21) had a decrease in PSA at their 2-month follow-up, with 66% (14 of 21) having a decrease of greater than 50% in PSA levels. At 24 months, two patients had a decrease of 20% to 50% in pretreatment PSA levels. In group three, 50% (2 of 4) had a decrease of greater than 50% in PSA levels at 2 months, and the remaining two patients had an increase at 2 and 6 months. Eighty-two percent of study patients had a decreased PSA level after 2 months of therapy. Side effects included nipple tenderness (42%), gynecomastia (8%), hot flashes, and deep venous thrombosis.[7] In both Germany and the United Kingdom, PC-SPES–like formulations have been studied. A phase I trial of PC-Spes2 in the United Kingdom encountered tolerability problems due to diarrhea.[8]

References:

1. Oh WK, Kantoff PW, Weinberg V, et al.: Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 22 (18): 3705-12, 2004.
2. Oh WK, George DJ, Hackmann K, et al.: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 57 (1): 122-6, 2001.
3. Pirani JF: The effects of phytotherapeutic agents on prostate cancer: an overview of recent clinical trials of PC SPES. Urology 58 (2 Suppl 1): 36-8, 2001.
4. Pfeifer BL, Pirani JF, Hamann SR, et al.: PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. BJU Int 85 (4): 481-5, 2000.
5. Small EJ, Frohlich MW, Bok R, et al.: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18 (21): 3595-603, 2000.
6. de la Taille A, Hayek OR, Buttyan R, et al.: Effects of a phytotherapeutic agent, PC-SPES, on prostate cancer: a preliminary investigation on human cell lines and patients. BJU Int 84 (7): 845-50, 1999.
7. de la Taille A, Buttyan R, Hayek O, et al.: Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 164 (4): 1229-34, 2000.
8. Shabbir M, Love J, Montgomery B: Phase I trial of PC-Spes2 in advanced hormone refractory prostate cancer. Oncol Rep 19 (3): 831-5, 2008.

Adverse Effects

Adverse effects of PC-SPES treatment were similar to those of hormonal drugs. The percentages indicate the approximate low-to-high range of side effects reported in the studies. It is difficult to compile accurate numbers from all studies reporting side effects because they are not consistently reported. Some studies concatenated categories of side effects, some did not report specific numbers or percentages, and some reported a few side effects while not reporting others. The following references indicate the studies from which the percentages come:

  • Gynecomastia (8%–8.7%).[1,2,3,4,5,6]
  • Nipple tenderness (34.8%–100%).[1,2,3,4,5,6,7]
  • Dyspepsia/nausea (15.7%–21.7%).[2,3,4,5,6,7]
  • Fatigue (8%–17.1%).[1,2,3,4,5]
  • Diarrhea (13%–38.6%).[1,2,3,4,5]
  • Leg cramps/swelling (2%–68.5%).[1,2,3,4,5]
  • Cardiovascular problems/angina (4.3%–7%).[1,2,3,4,5]
  • Hot flashes (4.3%–34%).[1,2,3,4,5]
  • Decreased libido (6.2%–100%).[5,7]
  • Erectile dysfunction (single case report).[8]
  • Thromboembolic effects (5%–6.2%).[5,6]

References:

1. Oh WK, George DJ, Hackmann K, et al.: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 57 (1): 122-6, 2001.
2. Oh WK, George DJ, Kantoff PW: Rapid rise of serum prostate specific antigen levels after discontinuation of the herbal therapy PC-SPES in patients with advanced prostate carcinoma: report of four cases. Cancer 94 (3): 686-9, 2002.
3. de la Taille A, Buttyan R, Hayek O, et al.: Herbal therapy PC-SPES: in vitro effects and evaluation of its efficacy in 69 patients with prostate cancer. J Urol 164 (4): 1229-34, 2000.
4. de la Taille A, Hayek OR, Buttyan R, et al.: Effects of a phytotherapeutic agent, PC-SPES, on prostate cancer: a preliminary investigation on human cell lines and patients. BJU Int 84 (7): 845-50, 1999.
5. Small EJ, Frohlich MW, Bok R, et al.: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 18 (21): 3595-603, 2000.
6. Pfeifer BL, Pirani JF, Hamann SR, et al.: PC-SPES, a dietary supplement for the treatment of hormone-refractory prostate cancer. BJU Int 85 (4): 481-5, 2000.
7. DiPaola RS, Zhang H, Lambert GH, et al.: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339 (12): 785-91, 1998.
8. Moyad MA, Pienta KJ, Montie JE: Use of PC-SPES, a commercially available supplement for prostate cancer, in a patient with hormone-naive disease. Urology 54 (2): 319-23; discussion 323-4, 1999.

Summary of the Evidence for PC-SPES

To assist readers in evaluating the results of human studies of complementary and alternative medicine (CAM) treatments for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

  • Be published in a peer-reviewed scientific journal.
  • Report on therapeutic outcome or outcomes, such as tumor response, improvement in survival, or measured improvement in quality of life.
  • Describe clinical findings in sufficient detail that a meaningful evaluation can be made.

The lack of consistent composition of PC-SPES due to varying concentrations of adulterants makes it difficult to determine the effects of PC-SPES in humans; therefore, no level of evidence analysis is possible for this treatment. At this time, the use of PC-SPES as a treatment for cancer cannot be recommended outside the context of well-designed clinical trials.

For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.

Changes to This Summary (08 / 07 / 2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of PC-SPES in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for PC-SPES are:

  • John A. Beutler, PhD (National Cancer Institute)
  • Jeffrey D. White, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® PC-SPES. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/cam/pc-spes/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Last Revised: 2013-08-07

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