Alkaloids fromCassytha filiformisand 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.

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“…This compound was also able to induce apoptosis in human promyelocytic leukemia cells via caspase-3 activation in a concentration-dependent manner [42]. Other promising cytotoxic agents included are six aporphines ( 05 – 10 ) from Cassytha filiformis , among which actinodaphnine ( 05 ), cassythine ( 06 ), and dicentrine ( 07 ) were also shown to possess antitrypanosomal properties in vitro on Trypanosoma brucei brucei [43]. Hypoestoxide (HE, 11 ), a natural diterpenoid [a bicyclo (9, 3, 1) pentadecane], derived from Hypoestoes rosea growing in Nigeria [44] has been reported to be a potent nonsteroidal anti-inflammatory drug.…”

Isocorydine Inhibits Cell Proliferation in Hepatocellular Carcinoma Cell Lines by Inducing G2/M Cell Cycle Arrest and Apoptosis

“…ICD treatment also imparted relaxant properties on the rat aorta [14]. Additionally, ICD can effectively bind to DNA, thus behaving as a typical intercalating agent [15].…”

Caracterización bioquímica de la enzima bifuncional dihidrofolato reductasa-timidilato sintasa de Leishmania (Viannia) y su evaluación como blanco molecular

“…Another mode of action could thus be involved (34). The mechanism of action of aporphine alkaloids seems to be related, at least in part, to the inhibition of topoisomerase II by DNA intercalation or minor groove binding (35,36). The identification of liriodenine as a strong topoisomerase II catalytic inhibitor and a topoisomerase II poison has led to the search for other topoisomerase II inhibitors among the aporphine alkaloids (35).…”