Abstract
Fungal, bacterial, and cancer cells can develop resistance against antifungal, antibacterial, or anticancer agents. Mechanisms of resistance are complex and often multifactorial. Mechanisms include: (1) Activation of ATP-binding cassette (ABC) transporters, such as P-gp, which pump out lipophilic compounds that have entered a cell, (2) Activation of cytochrome p450 oxidases which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) Activation of glutathione transferase, which can conjugate xenobiotics. This review summarizes the evidence that secondary metabolites (SM) of plants, such as alkaloids, phenolics, and terpenoids can interfere with ABC transporters in cancer cells, parasites, bacteria, and fungi. Among the active natural products several lipophilic terpenoids [monoterpenes, diterpenes, triterpenes (including saponins), steroids (including cardiac glycosides), and tetraterpenes] but also some alkaloids (isoquinoline, protoberberine, quinoline, indole, monoterpene indole, and steroidal alkaloids) function probably as competitive inhibitors of P-gp, multiple resistance-associated protein 1, and Breast cancer resistance protein in cancer cells, or efflux pumps in bacteria (NorA) and fungi. More polar phenolics (phenolic acids, flavonoids, catechins, chalcones, xanthones, stilbenes, anthocyanins, tannins, anthraquinones, and naphthoquinones) directly inhibit proteins forming several hydrogen and ionic bonds and thus disturbing the 3D structure of the transporters. The natural products may be interesting in medicine or agriculture as they can enhance the activity of active chemotherapeutics or pesticides or even reverse multidrug resistance, at least partially, of adapted and resistant cells. If these SM are applied in combination with a cytotoxic or antimicrobial agent, they may reverse resistance in a synergistic fashion.
Highlights
EVOLUTIONARY AND ECOLOGICAL BACKGROUND Plants are sessile organisms which cannot run away when attacked by an herbivore nor do they have an immune system to combat infesting parasites, bacteria, fungi, or viruses
Mechanisms include: (1) Activation of ATPbinding cassette (ABC) transporters, such as p-gp, which pump out lipophilic compounds that have entered a cell, (2) activation of cytochrome p450 oxidases (CYP) which can oxidize lipophilic agents to make them more hydrophilic and accessible for conjugation reaction with glucuronic acid, sulfate, or amino acids, and (3) activation of glutathione transferase (GST), which can conjugate xenobiotics with glutathione
Breast cancer resistance protein and P-gp are highly expressed at the apical membrane of blood–brain barrier (BBB), placenta, liver, intestine, and other organs (Schinkel and Jonker, 2003)
Summary
EVOLUTIONARY AND ECOLOGICAL BACKGROUND Plants are sessile organisms which cannot run away when attacked by an herbivore nor do they have an immune system to combat infesting parasites, bacteria, fungi, or viruses. SM which interfere with proteins, such as polyphenols, biomembranes (saponins and other lipophilic terpenoids), or DNA (alkylating or intercalating mutagens) affect a wider range of organisms, including animals and microbes. A large number of SM have lipophilic properties which enable them to readily pass biomembranes in target organisms by simple diffusion. These SM are dangerous for the producing plants. They are usually stored in dead tissue away from living cells, such as resin ducts, oil cells, trichomes, or cuticles (Wink, 2010b). The absorption of polar SM is usually slower or does not www.frontiersin.org
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