Mini-review
Bromelain’s activity and potential as an anti-cancer agent: Current evidence and perspectives
Introduction
Bromelain is an aqueous extract of pineapple that contains a complex mixture of thiol proteases and non-protease components. Proteases constitute the major components of bromelain and include stem bromelain (80%), fruit bromelain (10%), and ananain (5%). Among non-protease components are phosphatases, glucosidases, peroxidases, cellulases, glycoproteins and carbohydrates (reviewed in [1]). Assays for the individual protease components of bromelain have recently been established thus raising the possibility of standardizing bromelain preparations [2].
Bromelain can be absorbed in human intestines without degradation and without losing its biological activity [3]. Experiments in mice showed that antacids such as sodium bicarbonate preserve the proteolytic activity of bromelain in the gastrointestinal tract [4]. Taken orally, bromelain is well tolerated in high doses (up to 3 g/day) for prolonged periods of therapy, even up to several years (citations in [3], [5], [6], [7]).
The evidence for the anti-cancer activity of bromelain comes from traditional observations (in Southeast Asia), studies of animal- and cell-based models and anecdotal clinical studies. The anti-cancer activity of bromelain is attributed predominantly to its protease components [1].
So far, bromelain as a cancer treatment has not been the subject of randomized controlled clinical studies. Anecdotal clinical studies of bromelain carried out in the 1970s offer early evidence suggesting the effectiveness of high dosages of bromelain (1–2.4 g/day) for treating some cancers, including breast and ovarian (citations in [1]). In 1995, Zavadova et al. [8] suggested that bromelain (as part of the multienzyme preparation Wobenzym) increases neutrophil activity, based on a study using healthy volunteers taking bromelain orally. Eckert et al. [9], performed clinical studies involving breast cancer patients and healthy volunteers and observed the stimulation of immunocytotoxicity of cancer-patient-derived immune cells following oral administration of bromelain. Most of the other evidence for bromelain anti-cancer activity comes from in vivo studies involving mouse cancer models as well as from in vitro observations of human and mouse cells (cancer and normal) treated with bromelain preparations. These studies are discussed below.
More numerous than clinical studies of bromelain in cancer are clinical trials of bromelain showing its effectiveness for treating various inflammation-based conditions. These include breast engorgement during lactation [10], osteoarthritis of the knee and hip [11], [12], rhinosinusitis [13], sepsis in children [14] and urogenital inflammation [15]. Interestingly, no effect of bromelain was observed in the treatment of inflammation associated with relapsing multiple sclerosis, indicating the specificity of bromelain’s targets [16]. Other studies demonstrated bromelain’s anti-thrombotic, fibrinolytic, antiedematous properties and burn debridement properties (reviewed in [1], [17]). Though these are not cancerous conditions, these studies are nonetheless very important for an understanding of bromelain’s anti-cancer activity. Recent research has established that chronic inflammation, immune suppression as well as deregulation of the haemostatic system are implicated in carcinogenesis. These studies, therefore, allow one to speculate that bromelain targets the pathways that are directly involved in cancer initiation, growth and progression (the mechanisms of bromelain activity and its molecular and cellular targets are summarized in Table 1, Table 2).
Existing evidence indicates that bromelain can be a promising candidate for the development of future oral enzyme therapies for oncology patients. Previously, adjuvant therapy with external proteases has produced positive results in treating cancer, alleviating therapy side effects and prolonging survival [18]. Successful bromelain-based therapy development will be advanced by understanding the mechanisms of bromelain anti-cancer activity. In the following sections we will focus on evidence for the anti-cancer effects of bromelain that involve direct suppression of cancer cells as well as modulation of inflammatory, immune and haemostatic system function. In conclusion we will discuss directions for the further research and the prospects for the bromelain-based chemoprevention and adjuvant cancer therapy.
Section snippets
Growth and invasive capacity
The in vivo evidence is consistent in demonstrating the tumor-inhibitory effects of bromelain. In chemically-induced mouse skin papillomas, topical application of bromelain reduced tumor formation, tumor volume and caused apoptotic cell death [19]. These findings are in agreement with other observations of bromelain’s role in reducing metastasis [20] and of local tumor growth [20], [21], resulting in increased survival rates. The in vivo activity of bromelain however involves not only direct
The effect of bromelain on regulators of inflammation
Chronic inflammation contributes to the development of cancer during cellular transformation, survival, proliferation, invasion, angiogenesis and metastasis. The effects of chronic inflammation depend on the tumor type and the micro-environment of the tumor. The leading viewpoint suggests that control of chronic inflammation could reduce the incidence of cancer as well as inhibit cancer progression [26].
CD44
Among bromelain-sensitive surface markers is CD44. It is expressed by cancer and immune cells and is directly implicated in cancer growth and metastasis as well as in the regulation of lymphocyte recruitment to the vascular endothelium at the sites of inflammation [50], [51]. Accumulation of soluble CD44 in circulation was found to correlate with cancer aggressiveness and lymph node metastasis and serves as a diagnostic and prognostic marker [51], [52], [53].
Bromelain was shown to reduce CD44
Fibrinolytic effects
Elevated levels of soluble fibrin were found to be a prognostic marker for cancer progression. Fibrin is directly involved in inhibiting lymphocytes-tumor adhesion and decreasing cytotoxicity [72]. Additionally, tumor cells are believed to form a protective coat by polymerizing fibrin and human serum albumin. This coat is resistant to the proteolytic activity of internal proteases such as plasmin and provides tumor cells with protection against the immune system [73]. A recent study of the
Conclusion
Traditional and anecdotal clinical evidence suggest that bromelain could be an effective anti-cancer therapeutic agent. Laboratory evidence suggests that bromelain’s anti-cancer effect could be the result of a systemic response, possibly involving a variety of targets. A summary of bromelain-sensitive targets is presented in Table 1. Possible mechanisms mediating anti-cancer activity of bromelain together with the areas for future research are presented in Table 2.
The molecular mechanisms of
Conflicts of interest
None declared.
Acknowledgements
We would like to acknowledge the support of Prof. Ramlan Bin Abd. Aziz, director of Chemical Engineering Pilot Plant, University Technology Malaysia and Prof. Dr Mohammad Roji B. Sarmidi, Research and Development Manager of Chemical Engineering Pilot Plant, University Technology Malaysia from. Authors are very grateful to Dr Michael John Kooy for the help in preparation of the manuscript. The work is funded by the University Technology Malaysia.
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