Proteolytic enzymes

Health Care Professional Information

Brand Name

Wobenzym®, Wobe-Mugos®, Zymactive®

Clinical Summary

Proteolytic enzyme (PE) treatments were first popularized in Germany in the 1960s for inflammation, osteoarthritis, autoimmune diseases, and viral infections. The products usually contain a mixture of pancreatin, papain, bromelain, trypsin, and chymotrypsin. Studies done in vitro and in mice have shown that PEs have immunomodulatory and tumoricidal properties (1) (2) (3) (4) (5) (6). Such effects are thought to result from degradation of abnormal immune complexes.

Oral administration of PEs to healthy volunteers resulted in immunomodulatory effects (7). Although some clinical and epidemiological studies suggest beneficial effects with adjuvant PEs in patients with head and neck cancers (8), multiple myeloma (9), breast cancer (10), and cervical cancer (11), conflicting data do not support the findings (12). A randomized controlled trial also determined there is insufficient evidence that these enzymes can prevent mucositis (13). Further, results from a study involving patients with inoperable pancreatic cancer showed a decrease in overall survival and poorer quality of life with PEs compared with standard gemcitabine-based chemotherapy (14).

Food Sources

Pineapple stem is a good source of bromelain. Papain is obtained from the papaya plant and fruits.

Purported Uses
  • Cancer
  • Cancer treatment-related symptoms
  • Hepatitis C
  • High cholesterol
  • Immunomodulation
  • Inflammation
  • Viral infections
Constituents

Can vary greatly due to product ingredients, which usually contains a mixture of pancreatin, papain, bromelain, trypsin and chymotrypsin.

Mechanism of Action

PEs are thought to exert immunomodulatory effects by causing increased release of reactive oxygen species by polymorphonuclear leukocytes (7) or by production of tumor necrosis factor-alpha and interleukins IL-6 and IL-1B that cause cytotoxic effects (1) (2). The antiangiogenic effects that papain exhibits in VEGF-activated human endothelial cells is concentration-dependent and likely due to interference with AKT, MEK1/2 and SAPK/JNK phosphorylation (15). Bromelain has been shown to lower the tumorigenic/metastatic capacities of sarcoma L-1 cells (3). It also inhibited glioma cell migration and invasion by affecting expression of integrins, necessary for cellular migration and invasion (5). In B16 murine melanoma models, PEs inhibited metastasis by reducing expression of CD44 and CD54 molecules (6).

Contraindications

A healthcare professional should be consulted before use if you are pregnant or nursing, or have a bleeding disorder or liver damage.

Adverse Reactions
  • Mild to moderate gastrointestinal symptoms (16)
  • See also Bromelain
Herb-Drug Interactions

Anticoagulants (Warfarin): Products with bromelain may increase bleeding risk due to its antithrombotic effects (17).

See additional bromelain interactions.

Literature Summary and Critique

Chabot JA, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol. 2010 Apr 20;28(12):2058-63.

This controlled, observational study evaluated PE therapy compared with gemcitabine-based chemotherapy in patients with inoperable pancreatic cancer. Of 55 enrolled patients, 23 chose chemotherapy and 32 elected enzyme treatment that consisted of pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. The two groups had no statistically significant differences in quality of life or pathology at enrollment. At 1-year time point, researchers observed an increase in median overall survival (9.7 mo) and better quality of life (P<.01) in patients who chose gemcitabine-based chemotherapy compared with those in the PE group.

Dorr W, Herrmann T, Study G. Efficacy of Wobe-Mugos E for reduction of oral mucositis after radiotherapy: results of a prospective, randomized, placebo-controlled, triple-blind phase III multicenter study. Strahlenther Onkol. 2007;183:121-127.

This prospective, randomized, placebo-controlled, triple-blind phase III multicenter study evaluated the efficacy and safety of PEs (Wobe-Mugos® E containing papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg) to treat side effects associated with head-and-neck radiotherapy (RT) including oral mucositis. A total of 69 patients were enrolled, with 61 evaluable patients. The primary endpoint was the maximum mucositis score during weeks 1–6 of RT. Although the intervention was well tolerated, there were no between-group differences in the primary endpoint results. However, the intervention appeared to result in an earlier onset of mucositis, thus increasing the average scores over treatment duration. Investigators concluded the PE therapy did not confer any benefit for patients with RT-induced early oral mucositis.

Dosage (Inside MSKCC Only)
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References
  1. Desser L, Rehberger A, Paukovits W. Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro. Cancer Biother. Fall 1994;9(3):253-263.
  2. Desser L, Rehberger A. Induction of tumor necrosis factor in human peripheral-blood mononuclear cells by proteolytic enzymes. Oncology. 1990;47(6):475-477.
  3. Beuth J, Braun JM. Modulation of murine tumor growth and colonization by bromelaine, an extract of the pineapple plant (Ananas comosum L.). In Vivo. Mar-Apr 2005;19(2):483-485.
  4. Desser L, Rehberger A, Kokron E, et al. Cytokine synthesis in human peripheral blood mononuclear cells after oral administration of polyenzyme preparations. Oncology. Nov-Dec 1993;50(6):403-407.
  5. Tysnes BB, Maurer HR, Porwol T, et al. Bromelain reversibly inhibits invasive properties of glioma cells. Neoplasia. Nov-Dec 2001;3(6):469-479.
  6. Wald M, Olejar T, Sebkova V, et al. Mixture of trypsin, chymotrypsin and papain reduces formation of metastases and extends survival time of C57Bl6 mice with syngeneic melanoma B16. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S16-22.
  7. Zavadova E, Desser L, Mohr T. Stimulation of reactive oxygen species production and cytotoxicity in human neutrophils in vitro and after oral administration of a polyenzyme preparation. Cancer Biother. Summer 1995;10(2):147-152.
  8. Gujral MS, Patnaik PM, Kaul R, et al. Efficacy of hydrolytic enzymes in preventing radiation therapy-induced side effects in patients with head and neck cancers. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S23-28.
  9. Sakalova A, Bock PR, Dedik L, et al. Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S38-44.
  10. Beuth J, Ost B, Pakdaman A, et al. Impact of complementary oral enzyme application on the postoperative treatment results of breast cancer patients—results of an epidemiological multicentre retrolective cohort study. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S45-54.
  11. Dale PS, Tamhankar CP, George D, et al. Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S29-34.
  12. Martin T, Uhder K, Kurek R, et al. Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? Results of a double-blind randomized trial. Radiother Oncol. Oct 2002;65(1):17-22.
  13. Dorr W, Herrmann T, Study G. Efficacy of Wobe-Mugos E for reduction of oral mucositis after radiotherapy : results of a prospective, randomized, placebo-controlled, triple-blind phase III multicenter study. Strahlenther Onkol. Mar 2007;183(3):121-127.
  14. Chabot JA, Tsai WY, Fine RL, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. J Clin Oncol. Apr 20 2010;28(12):2058-2063.
  15. Mohr T, Desser L. Plant proteolytic enzyme papain abrogates angiogenic activation of human umbilical vein endothelial cells (HUVEC) in vitro. BMC Complement Altern Med. Sep 21 2013;13(1):231.
  16. Popiela T, Kulig J, Hanisch J, et al. Influence of a complementary treatment with oral enzymes on patients with colorectal cancers—an epidemiological retrolective cohort study. Cancer Chemother Pharmacol. Jul 2001;47 Suppl:S55-63.
  17. Metzig C, Grabowska E, Eckert K, et al. Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo. Jan-Feb 1999;13(1):7-12.

Consumer Information

How It Works

Bottom Line: Proteolytic enzymes have not been shown to treat cancer.

Proteolytic enzyme (PE) treatments were first used in Germany in the 1960s for inflammation, osteoarthritis, autoimmune diseases, and viral infections. The products usually contain a mixture of pancreatin, papain, bromelain, trypsin, and chymotrypsin. Laboratory studies have shown that PEs can affect the growth of cancer cells. Although PEs were reported to benefit patients with cancer, recent studies do not support such claims.

Purported Uses
  • Inflammation
    Observational studies suggest beneficial effects but clinical data are lacking.
  • Autoimmune diseases
    This use is not backed by clinical data.
  • Viral infections
    There is no scientific evidence to support this use.
  • Cancer and treatment-related symptoms
    Data from some studies suggest benefit, but more recent randomized controlled trials do not confirm this.
  • Hepatitis C
    This use is not supported by scientific evidence.
Research Evidence

Cancer Treatment
A total of 55 patients with inoperable pancreatic cancer were enrolled in this controlled, observational study. Twenty-three patients chose gemcitabine-based chemotherapy, and 32 chose enzyme treatment that consisted of pancreatic enzymes, nutritional supplements, detoxification, and an organic diet. The two groups had no significant differences in quality of life or pathology at enrollment. At the 1-year time point, researchers observed an increase in overall survival and better quality of life in patients who chose gemcitabine-based chemotherapy compared with those in the PE group.

Radiation Treatment Symptoms
A total of 69 patients were enrolled in this randomized controlled trial to see if PEs could treat the side effects associated with head and neck radiation, such as mouth ulcers and inflammation. Although PEs were well tolerated, there was no difference among those who took the enzymes, the placebo, or those who did not receive anything while undergoing radiation. In addition, radiation side effects started earlier in the PE group.

Do Not Take If
  • You are pregnant or breastfeeding: A healthcare professional should be consulted.
  • You have a bleeding disorder or liver damage: A healthcare professional should be consulted.
  • You are taking blood thinners: Product constituents may increase bleeding risk.
Side Effects
  • Gastrointestinal disturbance
  • See also Bromelain
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