title: Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases.
abstract: Cassytha filiformis (Lauraceae), a widely distributed parasitic plant, contains several aporphine alkaloids and is often used in African folk medicine to treat cancer, African trypanosomiasis and other diseases. In a previous investigation, we showed that the alkaloid plant extract and the isolated aporphines possessed in vitro cytotoxic properties. In this paper, we evaluated the in vitro activity of the alkaloid extract (IC50 = 2.2 microg/mL) and its three major aporphine alkaloids (actinodaphnine, cassythine, and dicentrine) on Trypanosoma brucei brucei as well as four related commercially available aporphines (bulbocapnine, glaucine, isocorydine, boldine). Only the three alkaloids from Cassytha filiformis were active on the trypanosomes in vitro (IC50 = 3-15 microM). Additionally, we compared the cytotoxicity of these seven compounds on HeLa cells. Glaucine was the most cytotoxic compound on HeLa cells (IC50 = 8.2 microM) in the series. In order to elucidate their mechanism of action, the binding mode of these molecules to DNA was studied by UV absorption, circular and linear dichroism spectroscopy. The results of the optical measurements indicated that all seven aporphines effectively bind to DNA and behave as typical intercalating agents. Biochemical experiments showed that actinodaphnine, cassythine and dicentrine also interfere with the catalytic activity of topoisomerases in contrast to the four other aporphines. These interactions with DNA may explain, at least in part, the effects observed on cancer cells and on trypanosomes.
authors.affiliation: Laboratoire de Pharmacognosie, Unité d'Analyse Chimique et Physico-Chimique des Médicaments, Université Catholique de Louvain, Bruxelles, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Hoet
authors.forename: Caroline
authors.initials: C
authors.lastname: Stévigny
authors.forename: Sébastien
authors.initials: S
authors.lastname: Block
authors.forename: Frederik
authors.initials: F
authors.lastname: Opperdoes
authors.forename: Pierre
authors.initials: P
authors.lastname: Colson
authors.forename: Brigitte
authors.initials: B
authors.lastname: Baldeyrou
authors.forename: Amélie
authors.initials: A
authors.lastname: Lansiaux
authors.forename: Christian
authors.initials: C
authors.lastname: Bailly
authors.forename: Joëlle
authors.initials: J
authors.lastname: Quetin-Leclercq
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001060:Aporphines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D019770:Lauraceae; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D059004:Topoisomerase I Inhibitors; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000517:prevention & control
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001060:Aporphines; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D059004:Topoisomerase I Inhibitors; D014344:Trypanocidal Agents