Digitonin synergistically enhances the cytotoxicity of plant secondary metabolites in cancer cells

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Date: Nov. 15, 2012
Publisher: Urban & Fischer Verlag
Document Type: Report
Length: 4,759 words
Lexile Measure: 1400L

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Keywords:

Digitonin

Phenolics

Terpenoids

Alkaloids

Synergy

ABSTRACT

In phytotherapy, extracts from medicinal plants are employed which contain mixtures of secondary metabolites. Their modes of action are complex because the secondary metabolites can react with single or multiple targets. The components in a mixture can exert additive or even synergistic activities. In this study, the cytotoxicity of some phytochemicals, including phenolics (EGCG and thymol), terpenoids (menthol, aromadendrene, [beta]-sitosterol-O-glucoside, and [beta]-carotene) and alkaloids (glaucine, harmine, and sanguinarine) were investigated alone or in combination with the cytotoxic monodesmo-sidic steroidal saponin digitonin in Caco-2, MCF-7, CEM/ADR5000, and CCRF-CEM cells. Digitonin was combined in non-toxic concentrations (5 [micro]M in each cell line: except in MCF-7 the concentration was 2[micro]M), together with a selection of phenolics, terpenoids, and alkaloids to evaluate potential synergistic or additive effects. An enhanced cytotoxicity was observed in most combinations. Even multi-drug resistant (MDR) cells (such as CEM/ADR5000 cells), with a high expression of P-glycoprotein, were responsive to combinations. Sanguinarine was the most cytotoxic alkaloid against CEM/ADR5000, MCF-7. and CCRF-CEM cells alone and in combination with digitonin. As compared to sanguinarine alone, the combination was 44.53-, 15.38-, and 6.65-fold more toxic in each cell line, respectively. Most combinations synergistically increased the cytotoxicity, stressing the importance of synergy when using multi-target drugs and mixtures in phytotherapy.

[c] 2012 Elsevier GmbH. All rights reserved.

Introduction

The main focus of drug development in the last 50 years has been on drugs which specifically interact with a single target (mono-target drugs). Mono-target drugs are excellent candidates for establishing structure-activity relationships. The therapeutical disadvantage of mono-target drugs concerns the fact that bacteria, viruses, parasites, and cancer cells often develop a resistance or tolerance against them. A promising alternative would be the use of combinations of two or several drugs, which affect the same or multiple targets (multi-target drugs) (Wagner 2011). Today, drug combinations are already applied successfully in the treatment of infectious diseases (including AIDS), hypertension, and many types of cancer and rheumatic diseases (Wagner 2011; Proudman et al. 2000). The advantages of using drug combinations include an increase of therapeutic efficacy, a decrease in the dose while maintaining the same effect with less toxicity, a reduction of drug resistance development, and potential synergistic effects (Chou 2006).

Synergy comes from the Greek word "synergos", which means working together. The common definition of synergy is 'an effect seen by a combination of substances that is greater than would have been expected from a consideration of individual contributions' (Heinrich et al. 2004). Synergy between secondary metabolites present in medicinal plants has been assumed to be a key for understanding the efficacy of traditional Chinese medicine (TCM) and European phytotherapy (Chou 2006).

The common classes of secondary metabolites (SMs) in medicinal plants which constitute their active principle, include phenolics, alkaloids, and terpenoids (Wink 2010). Among terpenoids, saponins represent the most common plant glycosides. The diversity of aglycones (steroidal ora triterpenoid) and the number and composition of the sugar side chains (consisting mainly of glucose, galactose, glucuronic acid, xylose,...

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Gale Document Number: GALE|A317589863