Digitonin synergistically enhances the cytotoxicity of plant secondary metabolites in cancer cells.
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, β-sitosterol-O-glucoside, and β-carotene) and alkaloids (glaucine, harmine, and sanguinarine) were investigated alone or in combination with the cytotoxic monodesmosidic steroidal saponin digitonin in Caco-2, MCF-7, CEM/ADR5000, and CCRF-CEM cells. Digitonin was combined in non-toxic concentrations (5μM in each cell line; except in MCF-7 the concentration was 2μM), 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.
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany. S.Eid@stud.uni-heidelberg.de
Safaa Yehia
SY
Eid
Mahmoud Zaki
MZ
El-Readi
Michael
M
Wink
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D053119:Benzophenanthridines / Q000494:pharmacology / Q000627:therapeutic use; D018938:Caco-2 Cells; D004070:Digitalis / Q000737:chemistry*; D004072:Digitonin / Q000494:pharmacology / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D013729:Terpenes / Q000494:pharmacology / Q000627:therapeutic use*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D007546:Isoquinolines; D010636:Phenols; D010936:Plant Extracts; D013729:Terpenes; C005705:sanguinarine; D004072:Digitonin