Proteolytic enzymes

• How It Works

  Proteolytic enzymes have not been shown to prevent or 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. But they may be useful in reducing pain associated with moderate-to-severe knee osteoarthritis.

• Purported Uses
  • Inflammation
    Observational studies suggest beneficial effects but clinical data are lacking.
  • Autoimmune diseases
    Evidence is lacking to support this claim.
  • Viral infections
    Evidence is lacking to support this claim.
  • Cancer and treatment-related symptoms
    Data from clinical studies are conflicting
  • Hepatitis C
    Evidence is lacking to support this claim.
• Do Not Take If

  You are taking anticoagulants (Warfarin): Bromelain may increase bleeding risk due to its antithrombotic effects observed in laboratory experiments and in mice ⁽¹⁷⁾. But clinical relevance is not known.

  See additional bromelain interactions.

• Side Effects
  • Gastrointestinal disturbance
  • See also Bromelain
• 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. Preclinical studies indicate 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.

  In clinical studies, oral administration of PEs to healthy volunteers resulted in immunomodulatory effects ⁽⁷⁾; and systemic therapy with a PE before and after exhaustive exercise increased maximal concentric strength, and had favorable effects on inflammatory, metabolic and immune biomarkers ⁽¹⁸⁾. In a randomized trial of subjects with moderate-to-severe knee osteoarthritis, oral PE was found to have comparable effectiveness as diclofenac in relieving pain and increasing function ⁽¹⁹⁾.

  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 failed to find sufficient evidence to support use of PEs for preventing 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⁾. But findings from two meta-analyses suggest that PEs may be useful for preventing acute radiation-induced skin reactions ⁽²⁰⁾. More studies are needed to confirm such effects.

• 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
• 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 anti-angiogenic effects exhibited by papain in VEGF-activated human endothelial cells are 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⁾.

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

  Anticoagulants (Warfarin): Bromelain may increase bleeding risk due to its antithrombotic effects observed in preclinical experiments ⁽¹⁷⁾. But clinical relevance is not known.

  See additional bromelain interactions.

• 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.

  18. Marzin T, Lorkowski G, Reule C, et al. Effects of a systemic enzyme therapy in healthy active adults after exhaustive eccentric exercise: a randomised, two-stage, double-blinded, placebo-controlled trial. BMJ Open Sport Exerc Med. 2017 Mar 12;2(1):e000191.

  19. Bolten WW, Glade MJ, Raum S, Ritz BW. The safety and efficacy of an enzyme combination in managing knee osteoarthritis pain in adults: a randomized, double-blind, placebo-controlled trial. Arthritis. 2015;2015:251521.

  20. Chan RJ, Webster J, Chung B, Marquart L, Ahmed M, Garantziotis S. Prevention and treatment of acute radiation-induced skin reactions: a systematic review and meta-analysis of randomized controlled trials. BMC Cancer. 2014 Jan 31;14:53.