Mechanism of action of cytotoxic compounds from the seeds of Euphorbia lathyris

Abstract

BackgroundThe seeds of Euphorbia lathyris are used in traditional Chinese medicines for the treatment of various medical conditions. E. lathyris contains many natural diterpenes with a lathyrane skeleton. Purpose and study designFive lathyrane-type diterpenoids named Euphorbia factors L1, L2, L3, L8, and L9 (1–5), were investigated for cytotoxicity against A549, MDA-MB-231, KB, and MCF-7 cancer cell lines and the KB-VIN multidrug resistant (MDR) cancer cell line. Also, a tetraol derivative (6) of Euphorbia factor L2 (2) was synthesized to assess the effect of hydroxy moieties. MethodsAn ethanolic extract of seeds of Euphorbia lathyris was prepared and separated into petroleum ether, EtOAc, n-butanol, and n-hexane extracts. The natural diterpenes were isolated by using silica gel and Sephadex LH-20 column chromatography as well as preparative thin-layer chromatography. Saponification of 2 gave tetraol derivative 6. Cytotoxic activity was determined by the sulforhodamine B (SRB) colorimetric assay. Mechanism of action studies focused on the impact of compounds on the cell cycle progression as well as cell morphology. ResultsCompound 5 exhibited the strongest cytotoxicity against all cell lines, while compound 2 showed selectivity against KB-VIN. In cells treated with 3 and 5, accumulation of G1 to early S phase cells was obvious, while no effect was seen on G2/M phase. ConclusionAnalysis of the screening data compared with compound structures suggested that the substitutions at C-3, C-5, C-7, and C-15 are critical for cytotoxicity, as well as cell type-selectivity. Furthermore, results of cytotoxic mechanism analysis demonstrated for the first time that compounds 3 and 5 disrupted normal cell cycle progression, whereas compounds 2‒5 induced obvious actin filament aggregation, as well as partial interference of the microtubule network.