[Sanguinarine and ellipticine cytotoxic alkaloids isolated from well-known antitumor plants. Intracellular targets of their action].
Common molecular and cellular targets for alkaloids sanguinarine and ellipticine, isolated from well-known antitumor plants (as well as from their various natural and synthetic derivatives), have been studied and described. Sanguinarine and ellipticine are characterized by significant biological activities including a high antitumor potential. Among the important targets of their action the following are to be noted. 1. DNA and other double helical polynucleotides. Due to the ability of DNA-intercalation sanguinarine, ellipticine and some of their derivatives can modify the double helical structures and topological forms of polynucleotides. The results of these modifications in intercalative complexes manifest themselves in the inhibition of numerous enzymatic reactions, dependent on the structures and topological forms of DNA and other polynucleotides. 2. ATP synthesis in mitochondria. Most of DNA-intercalators, including sanguinarine and ellipticine, belong to a group of penetrating (hydrophobic) cations, which are accumulated near the external side of inner mitochondrial membranes during the membrane energization. They neutralize negative charges, arising just as the inner mitochondrial membranes become energized. By this neutralization of membrane charges the ATP synthesis in inhibited and the oxidative phosphorylation renders to be uncoupled. All studied DNA-intercalators under certain conditions uncouple the mitochondrial oxidative phosphorylation. Apparent correlation between the agents' ability for DNA-intercalation and for mitochondrial ATP synthesis inhibition seems to be determined by the importance for both types of reactions of molecule hydrophobicity and positive charges. 3. Cholinesterase systems. Sanguinarine, ellipticine and some of their derivatives, like other DNA-intercalators studied, inhibit also the enzymatic activities of cholinesterase systems due to hydrophobicity and positive charges of their molecules. 4. Sanguinarine (and chelerythrine), are also capable of inhibiting the biological activity of SH-dependent enzymes and proteins. Due to the reactivity of iminium groups in sanguinarine and chelerythrine molecules with nucleophilic reagents, e.g. thiol groups of enzymes and other proteins, the activities of SH-enzymes and proteins are inhibited. In particular, sanguinarine and chelerythrine inhibit enzymatic activity of some SH-dependent ATPases, including membrane-bound cation-transport ATPases. The earlier accumulated experience of the application in medicine of plant saps and extracts containing these alkaloids, and of the treatment of many diseases (including benign and malignant tumors) by isolated alkaloids may be explained, to a certain extent, by the inhibition of activities of the above mentioned cellular targets. The selective toxicity of these alkaloids for the number of transformed cells can be explained in the same manner.
Faddeeva
M D
MD
Beliaeva
T N
TN
D000470:Alkaloids / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D053119:Benzophenanthridines; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004611:Ellipticines / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D007546:Isoquinolines; D008519:Medicine, Traditional; D010617:Phenanthridines / Q000494:pharmacology; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D010946:Plants, Medicinal / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000096:biosynthesis / Q000235:genetics
D000470:Alkaloids; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D002800:Cholinesterase Inhibitors; D004611:Ellipticines; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D007546:Isoquinolines; D010617:Phenanthridines; D010936:Plant Extracts; C034192:ellipticine; D004247:DNA; C005705:sanguinarine; C016299:chelerythrine; D000254:Sodium-Potassium-Exchanging ATPase