Mistletoe: From Mythology to Evidence-Based Medicine

K. S. Zänker, S. V. Kaveri

• Publisher: S. Karger
• Year: 2015
• ISBN:
  9783318054453
• Topic: Medizin
• Subtopic: Krankenpflege

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Zänker KS, Kaveri SV (eds): Mistletoe: From Mythology to Evidence-Based Medicine.
Transl Res Biomed. Basel, Karger, 2015, vol 4, pp 24-38 (DOI: 10.1159/000375423)

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The Anti-Cancer Activity of Mistletoe Preparations, as Related to Their Polyphenolic Profiles

Henning M. Schramm

Institute Hiscia, Society for Cancer Research, Arlesheim, Switzerland

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Abstract

Polyphenols are known for their specific anti-cancer prevention and therapy actions. Polyphenols are contained in mistletoe extracts at rather fairly high concentrations, and each mistletoe preparation has a specific flavonoid profile. The question arises whether polyphenols may contribute to the anti-tumoural therapeutic potential of these preparations. Indeed, in experimental and clinical studies, the anti-tumoural actions of mistletoe preparations and of various polyphenols concur to a large extent; this paper reviews and evaluates this issue. What makes polyphenols so interesting in oncology? Very distinctively, they act differently on malignant and normal cells: they exert cytotoxic, anti-angiogenetic, anti-hormonal, detoxicative and anti-inflammatory effects on cancer cells and carcinomas, whereas they do not affect, or even act cytoprotectively, on normal cells. The polyphenols in mistletoe do not exert their actions in isolation but in combination with other substances of the plant, and additive or synergistic activity may occur between these substances. Besides the various ingredients of mistletoe preparations that have been studied in relation to their immunological activities, the polyphenols contained in these preparations may contribute to combating dysfunctional metabolism in cancer cells, the tumour and the patient.

© 2015 S. Karger AG, Basel

Introduction

Although the polyphenols contained in various mistletoe preparations are known for their preventive and therapeutic anti-cancer activities, their putative roles in the anti-tumoural properties of these preparations have so far not been evaluated. Polyphenols, especially flavonoids, have unique and specific anti-tumoural modes of action that interfere with the metabolism of cancer cells and of the cancer-carrying organism, and this has elicited the interest of many oncology researchers [1]. More than 12,700 publications on flavonoids and cancer are listed in PubMed, underlining the amount of research already available on this issue.

Alongside the effect of mistletoe preparations on cancer-combating responses, the polyphenols contained in these preparations may likewise intervene in the metabolism of cancer cells and cancer patients. Various studies demonstrate, for example, that mistletoe preparations may attenuate deviant glucose and lipid metabolism in cancer cells and of the patient [2, 3]. The same has been found for polyphenols, suggesting they may contribute to the action of mistletoe preparations upon cancer metabolism.

Both types of substances reduce not only cancer risk but also cancer recurrence and mortality. When comparing the highest and lowest flavonoid nutritional intake groups, various studies found a reduction of risk, recurrence and mortality in breast, prostate and colorectal cancer patients that ranged from 30 to 60% [4-6]. Comparable results in breast cancer patients were obtained using long-term therapy with mistletoe preparations [7]. A further reduction in breast cancer mortality, decreasing to 91%, was observed when a diet rich in flavonoids was combined with a patient's regular physical activity [8].

The aim of this review is to assess and define the therapeutic role of flavonoids in the anti-tumoural activity of mistletoe preparations.

The Polyphenolic Constituents of Mistletoe Preparations

Depending on the mode of extraction, mistletoe preparations may contain different and varying amounts of polyphenols. Most mistletoe preparations used in cancer treatment are extracted by maceration, which transfers about one-third of the flavonoids contained in the plant [9]. Flavonoid profiles differ between European mistletoe preparations from deciduous and coniferous trees. The characteristic polyphenols of mistletoe preparations from deciduous trees include quercetin, gallic acid, and chlorogenic acid. Naringenin was not detected, but it is found in mistletoe preparations from coniferous trees, namely the pine [10-12]. Thus, although our knowledge on the composition of mistletoe preparations is somewhat limited, we consider quercetin and naringenin as the flavonoid substances chiefly responsible for the various metabolic anti-tumoural properties of their corresponding mistletoe preparations.

The polyphenol contents in Viscum album fermentatum (Iscador preparations) vary from 1.9 to 2.5% in a 20% concentration extract. On average, this corresponds to 380-492 µg/ml of polyphenols in a 2% (20 mg/ml) ampoule.

Metabolism, Energy Homeostasis and Cancer

Instead of gaining energy from oxidative phosphorylation like most normal cells, cancer cells get their energy mainly from aerobic glycolysis [13]. In addition to glucose metabolism, lipid metabolism is also dysfunctional in these cells. The beta-oxidation of fatty acids is reduced, or where it is increased, is uncoupled by UCP-2 to overcome the oxidative stress in cancer cells. Furthermore, the activity of fatty acid synthase is increased in many tumour cell types [14].

Oxidative stress plays an important role in the pathway of carcinogenesis, and it becomes even more important once a cell has switched to a malignant phenotype with the capacity for unlimited proliferation. In this case, the mitochondrial respiratory chain becomes dysfunctional and produces increasing amounts of reactive oxygen species (ROS) that have to be neutralised [13]. The cancer cell enhances the metabolic pathways required to neutralise ROS on the one hand and to form the metabolic intermediates necessary for the continuous proliferation of the cancer cell on the other hand.

This review will discuss how mistletoe preparations and polyphenols interfere with these metabolic pathways in a malignant cell.

Polyphenols Under Investigation in Oncology

In Asia, where, for example, the consumption of Genistein in soya products and cat-echins in green tea is high, much lower incidences of prostate cancer (25 times lower) and mammary cancers (10 times lower) were found in comparison to residents in western countries. These differences diminish substantially when Asians migrate to western countries and adopt a western lifestyle [15, 16]. Therefore, not only genetic factors but also specific different nutritional factors in Asia are considered to contribute to the reduced incidence of prostate and mammary cancer in these countries. Based on epidemiological studies, Doll and Peto estimated that an approximate average of 30-35% of all cancer deaths are attributable to nutrition [17, 18]. If dietary factors, including obesity and alcohol and tobacco consumption, are considered together, the percentage of cancer-related deaths that are attributable to them is as high as 60-90% [18].

These observations triggered a large number of epidemiological studies on the effect on cancer risk, recurrence and mortality from diets rich in polyphenols. Many of these studies showed not only a significant anti-tumoural activity but also varying susceptibility of the different cancer types to the diverse polyphenolic substances in the diet, a subject we will return to later.

Various in vitro and in vivo studies have demonstrated that polyphenols exert pro-apoptotic, anti-glycolytic, anti-lipogenic, anti-angiogenetic, anti-inflammatory, pro-and anti-oxidative, anti-aromatase, anti-oestrogenic and anti-fatigue activities. All of these modes of action, except the anti-oestrogenic and anti-aromatase activities, were, as we will refer to later, demonstrated using all mistletoe preparations. The possible hormonal activities of certain mistletoe preparations have so far not been investigated, and therefore this factor cannot be evaluated.

Some Distinctive Properties of Mistletoe Preparations and Polyphenols in Relation to Their Anti-Cancer Modes of Action

We focus here on the surprising and unique anti-tumoural mode of actions of polyphenols, which are distinct from most other chemotherapeutic substances applied in cancer treatment. Polyphenols interfere with the metabolism of cancer cells at various levels, whereas normal cells are unaffected by them. A majority of polyphenols, especially flavonols and flavones, exert their cytotoxic effects on the mitochondria of cancer cells via pro-oxidative properties, whereas they act as anti-oxidants at the same concentrations in normal cells [19-22]. Polyphenols exert anti-oestrogenic properties on breast cancer cells and at the same time act pro-oestrogenically on bone cells, thus stabilising them [23]. The flavonols and flavones inhibit fatty acid synthase without provoking weight loss that is potentially induced by synthetic inhibitors [24]. Various polyphenols depress the activity of enzymes in detoxification phase I, which are specifically overexpressed in cancer cells, whereas they stimulate enzymes in detoxification phase II, where lipophilic oncogenic substances are neutralised and excreted [25].

However, besides influencing the metabolism of cancer cells, polyphenols attenuate extreme metabolic conditions, such as obesity or underweight, which are risk factors for cancer.

The extent to which these distinctive properties have been demonstrated for mistletoe preparations is a question that will be discussed in the following sections.

Pro- or Anti-Oxidative Properties of Mistletoe Preparations and Polyphenols in Respect to Target Cells

The preventive effect of flavonoids on carcinogenesis is assumed to be mainly due to their anti-oxidative activity. However, in various cancer cell lines and in animal cancer studies, flavonoids, such as flavonols, catechins, and flavones, act pro-oxidatively in mitochondria and thus cause apoptosis of these malignant cells [20]. Flavonoids deplete glutathione, thiored...