title: Synergism of three-drug combinations of sanguinarine and other plant secondary metabolites with digitonin and doxorubicin in multi-drug resistant cancer cells.
abstract: We determined the ability of some phytochemicals, including alkaloids (glaucine, harmine, and sanguinarine), phenolics (EGCG and thymol), and terpenoids (menthol, aromadendrene, β-sitosterol-O-glucoside, and β-carotene), alone or in combination with the saponin digitonin to reverse the relative multi-drug resistance of Caco-2 and CEM/ADR5000 cells to the chemotherapeutical agent doxorubicin. The IC(50) of doxorubicin in Caco-2 and CEM/ADR5000 was 4.22 and 44.08μM, respectively. Combination of non-toxic concentrations of individual secondary metabolite with doxorubicin synergistically sensitized Caco-2 and CEM/ADR5000 cells, and significantly enhanced the cytotoxicity of doxorubicin. Furthermore, three-drug combinations (secondary metabolite+digitonin+doxorubicin) were even more powerful. The best synergist was the benzophenanthridine alkaloid sanguinarine. It reduced the IC(50) value of doxorubicin 17.58-fold in two-drug combinations (sanguinarine+doxorubicin) and even 35.17-fold in three-drug combinations (sanguinarine+digitonin+doxorubicin) in Caco-2 cells. Thus synergistic drug combinations offer the possibility to enhance doxorubicin efficacy in chemotherapy.
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany.
authors.forename: Safaa Yehia
authors.initials: SY
authors.lastname: Eid
authors.forename: Mahmoud Zaki
authors.initials: MZ
authors.lastname: El-Readi
authors.forename: Michael
authors.initials: M
authors.lastname: Wink
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / 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; D004072:Digitonin / Q000494:pharmacology / Q000627:therapeutic use*; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D010944:Plants / Q000737:chemistry; D013729:Terpenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D053119:Benzophenanthridines; D007546:Isoquinolines; D010636:Phenols; D010936:Plant Extracts; D013729:Terpenes; D004317:Doxorubicin; C005705:sanguinarine; D004072:Digitonin