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

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Dodatkowe info na temat Bromelina mozna znalesc tutaj:

Bromelain

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przedruk z:
http://www.insidershealth.com/article/a ... elain/2398

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.

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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] and [7]).

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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] E. Zavadova, L. Desser and T. Mohr, Stimulation of reactive oxygen species production and cytotoxicity in human neutrophils in vitro and after oral administration of a polyenzyme preparation, Cancer Biother. 10 (1995), pp. 147–152. View Record in Scopus | Cited By in Scopus (22)[8] suggested that bromelain (as part of the multienzyme preparation Wobenzym) increases neutrophil activity, based on a study using healthy volunteers taking bromelain orally. (...)

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2.2. Apoptosis and cell survival

Bromelain was shown to increase expression of p53 as well as another activator of apoptosis, Bax, in mouse skin papillomas [19]. At the same time, bromelain decreased the activity of cell survival regulators such as Akt and Erk thus promoting apoptotic cell death in tumors.

In agreement with the previous observations, bromelain’s effect on cell survival regulators was shown to be cell context-dependent. In mouse cardiomyocytes, bromelain increased cell survival and decreased apoptotic cell death leading to protection against ischemia–reperfusion injury. Here bromelain activated the cell survival mediator Akt and deactivated Akt-dependent pro-apoptotic regulator FOXO3A [25].

3. 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].

3.1. NF-κB, Cox-2 and PGE2

There is accumulating evidence showing the role of NF-κB signaling and over-expression in many types of cancers [26] and [27]. Emerging evidence also suggests that depending on cell context, NF-κB can also promote tumor suppression [28]. Among multiple target genes of NF-κB is Cox-2, a key player in chronic and cancer-related inflammation [29] and [30]. Cox-2 is involved in the synthesis of prostaglandin E2 (PGE2), a pro-inflammatory lipid that also acts as an immunosuppressant and promoter of cancer progression. By facilitating conversion of arachidonic acid into PGE2, Cox-2 was shown to promote tumor angiogenesis and progression [30]. It is considered that inhibiting NF-κB, Cox-2 and PGE2 activity has potential as a treatment of cancer and chronic inflammatory diseases.

Bromelain was shown to down-regulate NF-κB and Cox-2 expression in mouse papillomas [19] and in models of skin tumorigenesis [31]. Additionally, in human monocytic leukemia and murine microglial cell lines, bromelain was shown to inhibit bacterial endotoxin (LPS)-induced NF-κB activity as well as the expression of PGE2 and Cox-2 [32]; [33].

Molecular mechanisms mediating this effect of bromelain are still unknown. We hypothesize that bromelain-induced cleavage of cell surface markers such as CD14 [32] could initiate an intracellular cascade that negatively regulates inflammation-induced NF-κB activation and its target genes. One of the interesting possibilities to investigate is whether bromelain generates cell-permeable peptide fragments similar to the synthetic NF-κB essential modulator-binding domain peptides that possess NF-κB suppressing capacity [34].

3.2. IFNγ, TNF-α, IL-1β and IL-6

Among the secreted regulators of inflammation that are connected to NF-κB pathways and that respond to bromelain are IFNγ, TNF-α, IL-1β and IL-6. Depending on the context and micro-environment, these regulators can either stimulate tumor growth and invasion or activate immune responses and cause tumor regression [35], [36], [37] and [38].

Experimental evidence derived from analyzing peripheral blood mononuclear cells (PBMC) from healthy volunteers as well as mouse macrophages suggested that bromelain can activate TNF-α, IL-1β and IL-6 secretion in an IFNγ-dependent mechanism [39], [40] L. Desser, A. Rehberger and W. Paukovits, Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro, Cancer Biother. 9 (1994), pp. 253–263. View Record in Scopus | Cited By in Scopus (25)[40], [41] and [42]. IFNγ production, in turn, was also increased in the presence of bromelain [42]. These data allow us to hypothesize that bromelain has the potential to activate healthy immune system to ensure rapid response to pathogens and cellular stress.

However, in situations when immune cells are already stimulated, bromelain reduces TNF-α, IL-1β and IL-6 secretion. This occurs in the conditions of inflammation-induced over-production of cytokines. For instance, in the presence of LPS, which has the capacity to stimulate an acute inflammatory reaction, bromelain reduced elevated TNF-α, IL-1β and IL-6 expression in human PBMC [32]. A similar effect was observed in LPS-stimulated human monocytic leukemia cell lines [32]. Reduction of TNF-α and IFNγ expression was also observed in bromelain-treated inflamed tissues obtained from patients with inflammatory bowel disease (IBD) [43].

The described data demonstrate that the effects of bromelain on cytokine expression depend on the presence of inflammation-inducing conditions. This underlines the potential of bromelain for treatment of inflammation-based pathologies. Further studies with cancer patient-derived immune cells and tumor samples are required for further elucidation of bromelain effects on cancer-induced inflammation and immune suppression.
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4.4. Reactive oxygen species (ROS)

Bromelain can stimulate the innate immune system by activating neutrophils to produce ROS. As part of a polyenzyme preparation, bromelain was shown to stimulate ROS production and tumor cell killing properties in neutrophils in vitro as well as in neutrophils from healthy volunteers taking the polyenzyme preparation [8] and [65]. ROS are also known to act as intracellular regulators of functional activity in neutrophils and other cell types including cancer [66] and [67]. Bromelain’s capacity to change intracellular levels of ROS would have a direct impact on the modulation of signaling both in immune and cancer cells.

These data however cannot be easily interpreted as beneficial for cancer control. There is ample evidence suggesting that activated neutrophils and excessive ROS production induce DNA damage and cancer pathogenesis. Thus increased production of ROS leads to oxidative stress conditions that are beneficial for cancer [68]. Additionally, recent studies suggest that cancer cells increase functional activity of neutrophils including ROS production [69]. However considering overall anti-cancer properties of bromelain and its environment- and cell status-determined activity it could be speculated that bromelain’s activity on ROS production in cancer patient-derived cells may be directed towards cancer inhibition. Further studies are necessary to elucidate these mechanisms.