Dehydroleucodine, a Sesquiterpene Lactone from Gynoxys verrucosa, Demonstrates Cytotoxic Activity against Human Leukemia Cells

Abstract

The sesquiterpene lactones dehydroleucodine (1) and leucodine (2) were isolated from Gynoxys verrucosa, a species used in traditional medicine in southern Ecuador. The activity of these compounds was determined against eight acute myeloid leukemia (AML) cell lines and compared with their activity against normal peripheral blood mononuclear cells. Compound 1 showed cytotoxic activity against the tested cell lines, with LD50 values between 5.0 and 18.9 μM. Compound 2 was inactive against all of the tested cell lines, demonstrating that the exocyclic methylene in the lactone ring is required for cytotoxic activity. Importantly, compound 1 induced less toxicity to normal blood cells than to AML cell lines and was active against human AML cell samples from five patients, with an average LD50 of 9.4 μM. Mechanistic assays suggest that compound 1 has a similar mechanism of action to parthenolide (3). Although these compounds have significant structural differences, their lipophilic surface signatures show striking similarities.

Synergistic activity of parthenolide and cytarabine in acute promyelocytic leukemia HL-60 cell line

“…This compound belongs to the group of sesquiterpene lactones. Thus, it has an α-methylene-g-lactone moiety with an alkylating activity and α-β-unsaturated cyclopentanone rings [8,9] . These chemical groups are assigned a role in biological activity of sesquiterpene lactones and they can be responsible for the mechanism of the antitumor action of PTL [9] .…”

The Effects of Artemisia Derived Natural Products on Adipogenesis

“…The plausibility of this biphasic effect is enhanced by DhL's similar structure to parthenolide, which has been hypothesized to result in similar functions for the two sesquiterpene lactones (Ordonez et al 2016). The functional moiety responsible for this activity is likely the exocyclic methylene group (Ordonez et al 2016). Both parthenolide and DhL possess this moiety, which is lacking (and the only structural difference between it and DhL) in leucodine.…”

“…Both parthenolide and DhL possess this moiety, which is lacking (and the only structural difference between it and DhL) in leucodine. Parthenolide and DhL both exhibit cytotoxic activity against acute myeloid leukemia (AML) cell lines by inducing apoptosis, whereas leucodine does not (Ordonez et al 2016). Both compounds downregulate the p65 transcription factor, which is essential for NF-κB activation (Ordonez et al 2016).…”

“…Parthenolide and DhL both exhibit cytotoxic activity against acute myeloid leukemia (AML) cell lines by inducing apoptosis, whereas leucodine does not (Ordonez et al 2016). Both compounds downregulate the p65 transcription factor, which is essential for NF-κB activation (Ordonez et al 2016). Furthermore, surface signature analysis of both molecules using their X-ray crystal structures reveals that the areas of greatest functional similarity include the excoyclic methylene group, and consist of the convex lipophilic parts of each molecule (Ordonez et al 2016).…”

“…Both compounds downregulate the p65 transcription factor, which is essential for NF-κB activation (Ordonez et al 2016). Furthermore, surface signature analysis of both molecules using their X-ray crystal structures reveals that the areas of greatest functional similarity include the excoyclic methylene group, and consist of the convex lipophilic parts of each molecule (Ordonez et al 2016). This may indicate that the binding areas of DhL to molecular actors in the adipogenic program may consist of lipophilic regions.…”