Bromelain’s activity and potential as an anti-cancer agent: Current evidence and perspectives

Abstract

The medicinal qualities of pineapple are recognized in many traditions in South America, China and Southeast Asia. These qualities are attributed to bromelain, a 95%-mixture of proteases. Medicinal qualities of bromelain include anti-inflammatory, anti-thrombotic, fibrinolytic and anti-cancer functions. Existing evidence derived from clinical observations as well as from mouse- and cell-based models suggests that bromelain acts systemically, affecting multiple cellular and molecular targets. In recent years, studies have shown that bromelain has the capacity to modulate key pathways that support malignancy. It is now possible to suggest that the anti-cancer activity of bromelain consists in the direct impact on cancer cells and their micro-environment, as well as in the modulation of immune, inflammatory and haemostatic systems. This review will summarize existing data relevant to bromelain’s anti-cancer activity and will suggest mechanisms which account for bromelain’s effect, in the light of research involving non-cancer models. The review will also identify specific new research questions that will need to be addressed in order for a full assessment of bromelain-based anti-cancer therapy.

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.